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Abstract Background: CD34+ hematopoietic stem and progenitor cell (HSPC) dose during hematopoietic cell transplantation (HCT) remains one of the most reliable clinical parameters to predict quality of engraftment. A minimum HSPC dose of 2-2.5x10 6 CD34+ cells/kg is considered necessary for reliable engraftment, while optimal doses of 5-6x10 6 CD34+ cells/kg are associated with faster engraftment, as well as fewer transfusions, infections, and antibiotic days. CXCR4 inhibition significantly improves the number (#) of CD34+ HSPCs mobilized for HCT, when added to G-CSF (G). Motixafortide (M), a novel CXCR4 antagonist, is a potent mobilizer of HSPCs recently evaluated in the phase 3, double blind, placebo controlled, multicenter GENESIS Trial as a mobilizing agent prior to autologous HCT (ASCT) in multiple myeloma (MM). Methods: Patients received G (10 mcg/kg) on days 1-5 (and days 6-8, if needed). On day 4 (and day 6, if needed), patients received either M (1.25 mg/kg) or placebo (P). Apheresis began day 5, with up to 4 days of apheresis if needed. The primary and secondary endpoints were collection of ³6x10 6 CD34+ cells/kg in up to 2 days of apheresis or 1 day, respectively. The # of CD34+ cells/kg infused was determined independently by each investigator according to local practice, but a minimum of ³2x10 6 CD34+ cells/kg was required. A post-hoc analysis was performed pooling data from both arms to evaluate time to platelet engraftment (TPE) (≥20x10 9/L without transfusions x7 days) and neutrophil engraftment (TNE) (ANC ≥0.5x10 9/L x3 days) based on total # of CD34+ cells/kg and # of specific CD34+ HSPC subsets infused. CD34+ HSPC immunophenotyping was performed via multicolor fluorescence-activated cell sorting (FACS). TPE/TNE was analyzed using Kaplan-Meier curves and Cox proportional hazards model. Results: 114 MM patients underwent apheresis, ASCT and were evaluable (M+G N=77; P+G N=37). M+G mobilization yielded a median of 10.8x10 6 CD34+ cells/kg collected in 1 apheresis vs 2.3x10 6 CD34+ cells/kg with P+G (p<0.0001). M+G also resulted in mobilization of higher #s of relevant CD34+ HSPC subsets vs P+G, including 5.6 fold more HSCs (CD45RA-CD123loCD38+CD90+CD49f+) (p<0.0001), 3.5 fold more multipotent progenitors (MPPs) and common myeloid progenitors (CMPs) (CD45RA-CD123loCD38+CD90-CD49f+) (p=0.0004) and 5.6 fold more granulocyte and macrophage progenitors (GMPs) (CD45RA+CD123loCD38+/-CD10-) (<0.0001). The median # of infused HSPCs in both arms was <6x10 6 CD34+ cells/kg (Table 1), with similar TPE of 17-18 days (HR 0.89, 95% CI 0.59-1.34, p=0.57) and TNE of 12 days (HR 0.94, 95% CI 0.62-1.41, p=0.75). However, pooled analysis of all patients (N=114) revealed infusion of ³6x10 6 CD34+ cells/kg was associated with faster median TPE of 16 days vs 18 days with <6x10 6 CD34+ cells/kg (HR 0.63, 95% CI 0.41-0.96, p=0.03) (Figure 1A). Further analysis demonstrated an inverse correlation between increasing CD34+ cells/kg infused and TPE (Pearson r=-0.2789, p=0.0027). In addition, pooled analysis of 36 patients (M+G N=24; P+G N=12) using extended multicolor FACS revealed infusion of higher #s (>75 th percentile) of combined CD34+ HSC, MPP, CMP and GMP subsets was associated with faster TPE of 12 days vs 19 days with lower #s of these subsets (p=0.003) (Figure 2A). Furthermore, higher #s (>75 th percentile) of GMPs was individually associated with faster TPE of 13 days vs 19 days with lower GMP cell doses (p=0.0116) (Figure 2C). TNE was not impacted by increasing doses of total CD34+ HSPCs or any specific CD34+ HSPC subset (all p>0.05) (Figures 1B, 2B and 2D). Conclusions: M+G mobilization enabled significantly more CD34+ cells to be collected in 1 apheresis (median 10.8x10 6 CD34+ cells/kg) vs P+G (2.3x10 6 CD34+ cells/kg), as well as 3.5-5.6 fold higher #s of HSCs, MPPs, CMPs and GMPs (all p-values <0.0004). This high # of CD34+ cells/kg mobilized with M+G enables the potential infusion of ≥6x10 6 CD34+ cells/kg and cryopreservation of cells for later use. A dose response was observed with significant correlation between faster TPE and infusion of higher #s of total CD34+ HSPC doses (³6x10 6 CD34+ cells/kg) and combined HSC, MPP, CMP and GMP subsets. Additionally, infusion of higher #s of CD34+ GMP subsets was independently associated with faster TPE, suggesting these more committed progenitors may play a critical role in early engraftment. Figure 1 Figure 1. Disclosures Crees: BioLineRx Ltd.: Research Funding. Retting: BioLineRx Ltd.: Research Funding. Larson: TORL biotherapeutics: Current holder of individual stocks in a privately-held company; Abbvie, Bioline, BMS, Celgene, GSK, Janssen, Juno, Novartis, Pfizer, Takeda: Research Funding. Illes: Novartis, Janssen, Pfizer, Roche: Other: Travel, Accommodations, Expenses; Takeda, Seattle Genetics: Research Funding; Janssen, Celgene, Novartis, Pfizer, Takeda, Roche: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding. Sborov: SkylineDx: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pereira: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Mikala: Abbvie: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Krka: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Holtick: Sanofi: Honoraria; Celgene: Honoraria. Qazilbash: Janssen: Research Funding; Oncopeptides: Other: Advisory Board; Biolline: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding. Hardy: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; American Gene Technologies, International: Membership on an entity's Board of Directors or advisory committees; InCyte: Membership on an entity's Board of Directors or advisory committees. Sorani: BioLineRx LTD: Current Employment. Shemesh-Darvish: BioLineRx LTD: Current Employment. Vainstein: BioLineRx LTD: Current Employment; Enlivex: Consultancy. Kadosh: StatExcellence: Current holder of individual stocks in a privately-held company; BioLineRx: Honoraria.

Abstract Introduction: Up to 40% of newly diagnosed diffuse large B cell lymphoma (DLBCL) will relapse after frontline rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (RCHOP), with subsequent poor prognosis. Identification of patients (pts) at high risk of relapse early in the treatment can allow for development of risk adapted therapies to improve outcomes. Positron Emission Tomography scan after 2 cycles of therapy (PET2) has been evaluated as a predictor of relapse but study treatments were heterogenous and results were conflicting. A substudy of CALGB 50303 trial did not find association of PET2 response by Deauville Score (DS) with survival in RCHOP and DA-EPOCH-R treated pts. In the UK National Cancer Research Institute Prospective Study, DS of 5 on PET2 predicted worse progression free survival but not overall survival (OS) in RCHOP-21 and RCHOP-14 treated pts. Here we report impact of PET2 response on outcomes in two large independent, prospective cohorts of newly diagnosed DLBCL treated homogenously with two RCHOP-based regimens of similar efficacy. Methods: Discovery was done in adult pts with DLBCL enrolled into a single arm phase 2 trial of lenalidomide plus standard RCHOP (R2CHOP) (MC078E, NCT00670358). The validation cohort comprised of adult pts with newly diagnosed DLBCL treated with standard RCHOP prospectively enrolled into the Mayo component of the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER). Both MC078E and MER cohorts included patients who received at least 3-6 cycles of therapy and had a PET2. Pts who progressed on PET2 were excluded. End of treatment (EOT) PET was done 3-12 weeks after last cycle of therapy. The revised response criteria for malignant lymphoma (Cheson, et al 2007) was used to assess PET in MC078E. In MER, revised response criteria for malignant lymphoma (Cheson et al 2007) or Lugano classification was used, depending on era of diagnosis. Positive PET was defined as FDG uptake above background (Cheson 2007) or DS 4 or 5 (Lugano 2014). Study endpoints were event-free survival (EFS) and OS by PET2 status. Results: Out of 118 pts treated on MC078E, 102 had PET2 (MC078E). The median age at diagnosis was 64 years (range 19-87), 61 (60%) were male, 89 (87%) had advanced stage disease, 46 (45%) had international prognostic index (IPI) of 3-5. 58 (57%) were PET2 Negative (PET2-ve) and 44 (43%) were PET2 Positive (PET2+ve). At EOT PET, 83 (81%) had -ve PET and 15 (15%) had +ve PET. Out of 44 PET2+ve pts, 15 remained +ve at EOT PET. Out of 58 PET2-ve pts, 56 had EOT PET available and all were -ve. Out of 866 DLBCL pts enrolled into MER between August 2005 and June 2015, 621 were treated with RCHOP for 3-6 cycles and 272 had available PET2 (MER). The median age was 65 years (range 55-73), 152 (56%) were male, 174 (64%) had advanced stage, 103 (38%) had IPI 3-5. 186 (68%) were PET2-ve and 86 (32%) were PET2+ve. Out of 235 with EOT PET available, 182 (77%) had -ve EOT PET and 25 (11%) had +ve EOT PET. PET2+ve pts had higher odds of +ve EOT PET (OR: 17.4 (CI 95 8.3-40.0), p<0.001) and progression on EOT PET (OR: 4.3 (CI 95 1.9-10.2), p<0.001) in MER cohort. This analysis was not possible on MC078E as all PET2-ve had -ve EOT PET. In MC078E, 2-year EFS and OS were 69.5% (CI 95 61.1-79.1) and 88.1% (CI 95 82-94.7). In MER, 2-year EFS and OS were 71.6% (CI 95 67.7-76.8) and 82.3% (CI 95 79.3-85.3). Compared to PET2-ve, PET2+ve pts had significantly inferior EFS in both MC078E (HR 4.0, CI 95 2.1-7.88, p<0.0001, figure 1a) and MER (HR 2.9, CI 95 1.9-4.1, p<0.0001, figure 1c). Compared to PET2-ve , PET2+ve pts had a trend towards lower OS in MC078E (HR 2.0, CI 95 0.9-4.9, p=0.1, figure 1b) and a significantly lower OS in MER (HR 2.3, CI 95: 1.5-3.4, p<0.0001, figure 1d). In subgroup analysis of MC078E, PET2+ve pts had lower EFS and a trend towards lower OS in all subgroups except IPI 0-2 (Table 1). In MER, PET2+ve pts had lower EFS and OS in all the subgroups except stage I-II and IPI 0-2 (Table 1). Conclusions: Positive PET2 was associated with increased risk of disease progression and death in newly diagnosed DLBCL. Results of our study provide robust evidence of importance of PET2 as an early predictor DLBCL pts at high risk of progression in two independent prospective cohorts. PET2-guided risk-adapted strategies using chimeric antigen receptor T-cell therapy and bispecific antibodies may potentially improve outcomes, should be explored in clinical trials and results of our study serve as a benchmark for such studies. Figure 1 Figure 1. Disclosures Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Nanostring: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang: Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; MorphoSys: Research Funding; InnoCare: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Regeneron Genetics Center: Other: Research Collaboration; NanoString: Research Funding; Genentech: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding; Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Our group published a double blind, randomized phase III study (Porrata et al, BBMT 2016; 22: 1017-1023) showing that the infusion of autograft absolute lymphocyte count (A-ALC) ≥ 0.5 x 10 9 cells/kg is a survival prognostic factor for lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). However, a limitation of the study was the short-term follow-up duration of two years post-APBHSCT. To assess if the A-ALC still provide survival benefit we looked at the 121 lymphoma patients enrolled in the phase III from December 10, 2007 until October 12, 2010 survival outcomes with a longer follow-up duration of up to 13 years post-APBHSCT. Since the accrual for the study, 52 patients had died of recurrence lymphoma, 4 patients of therapy-related acute myelogenous leukemia, 3 patients of unknown causes, 1 patient of acute respiratory distress syndrome, 1 patient of anaplastic astrocytoma, and 1 patient of septic shock. The current median follow-up is 86 months (range: 2.1-158.1 months) for the entire cohort and 127.8 months (range: 5.9-158.1 months) for patients still alive. Patients infused with an A-ALC ≥ 0.5 x 10 9 cells/kg continue to experience superior overall survival (OS) (HR = 0.392, 95%CI 0.224-0.687, P < 0.001) and progression-free survival (PFS) (HR = 0.413, 95%CI 0.253-0.677, P < 0.0004). The 10-year OS rates for the A-ALC ≥ 0.5 x10 9 cells/kg patients was 70% (95% confidence interval [CI], 55%-81%) and for the A-ALC < 0.5 x10 9 cells/kg patients was 36% (95% CI, 25%-49%) (Figure 1A). The 10-year PFS rates for the A-ALC ≥ 0.5 x10 9 cells/kg group was 57% (95% CI, 43%-70%) and for the A-ALC < 0.5 x10 9 cells/kg group was 28% (95% CI, 19%-40%) (Figure 1B). Autograft lymphocyte subset analysis including autograft-CD3 (A-CD3), autograft CD4 (A-CD4), autograft CD8 (A-CD8), and autograft natural killer cells (A-NK), showed that the infusion of A-NK was a predictor for OS (HR = 0.518, 95%CI 0.292-0.919, P < 0.02) and PFS (HR = 0.393, 95%CI 0.230-0.670, P < 0.0006). The 10-year OS rates for the A-NK ≥ 0.09 x10 9 cells/kg patients was 67% (95% confidence interval [CI], 50%-80%) and for the A-NK < 0.09 x10 9 cells/kg patients was 42% (95% CI, 31%-54%) (Figure 1C). The 10-year PFS rates for the A-NK ≥ 0.09 x10 9 cells/kg group was 59% (95% CI, 43%-73%) and for the A-NK < 0.09 x10 9 cells/kg group was 32% (95% CI, 23%-44%) (Figure 1D). Both the A-ALC and A-NK were independent predictor for OS [ A-ALC: HR = 0.367, 95%CI 0.195-0.690, P < 0.001) and A-NK: HR = 0.411, 95%CI 0.275-0.892, P < 0.01] and for PFS [ A-ALC: HR = 0.477, 95%CI 0.271-0.840, P < 0.01) and A-NK: HR = 0.490, 95%CI 0.266-0.903, P < 0.02]. With a longer follow-up of 13 years, this study shows that the infusion of A-ALC continues to provide better clinical outcomes to lymphoma patients undergoing APBHSCT. These study findings support our standard practice changed of not only collecting CD34 stem cell for hematologic engraftment, but also A-ALC for lymphoma patients undergoing APBHSCT to improve clinical outcomes. Further, autograft immune effector studies are warranted such as A-NK to develop a more immunocompetent targeted autologous graft verus tumor effect. Figure 1 Figure 1. Disclosures Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Paludo: Karyopharm: Research Funding.

Abstract Introduction: Clinical trials of novel salvage therapies (ST) have encouraging outcomes for relapsed/refractory classic Hodgkin lymphoma (R/R cHL) after autologous stem cell transplant (ASCT); yet studies comparing novel ST with conventional salvage chemotherapy are lacking. In a single center cohort, we demonstrated that bendamustine/brentuximab (BBV) had higher overall response rates (ORR) and complete response (CR) rates in ASCT-eligible R/R cHL (Desai et al JCO, 2021). Herein we report comparative outcomes of novel and conventional ST in R/R cHL who undergo ASCT, in a large multicenter retrospective cohort. Methods: Consecutive R/R cHL pts who underwent ASCT at 12 institutions across United States were included. Demographics and clinical variables at relapse including age, sex, B symptoms, stage, bulky disease (BD, single mass > 6 cm) extra nodal disease (END), primary refractory disease (PRD) and early relapse (ER, within 1 year) were recorded by electronic health records review. Study objectives were ORR, CR to first ST, post-ASCT PFS and OS by final ST. Time to event endpoints were defined from date of ASCT. Results: From 12 participating institutions, 853 pts of R/R cHL who underwent ASCT were eligible for this study. Median age was 33 (14-72) years, 457 (54%) were male, 446 (52%) had BD, 257 (30%) had advanced stage, 271 (32%) had END, 369 (43%) had B symptoms, 142 (17%) had PRD and 307 (36%) had ER. All 853 received at least 1 ST, 245 received 2 ST, 71 received 3 ST and 26 received 4 ST. Seven groups of ST were identified: 1. Conventional platinum-based chemotherapy (PBC) group including ICE, DHAP and ESHAP 2. BBV 3. Brentuximab Vedotin and nivolumab (BV/Nivo) 4. BV alone (BV) 5. gemcitabine-based chemotherapy (Gem) 6. checkpoint inhibitors (CPI) and 7. other miscellaneous agents (Misc). 1st ST was as follows: 553 had PBC; 69 had BBV; 48 had BV/Nivo; 65 had BV; 49 had Gem; 4 had CPI and 63 had Misc. There was no significant difference in the baseline characteristics by type of 1 st ST (data not shown). BBV had significantly higher ORR (92% vs 79%, p<0.001) and CR rate (80% vs 49%, p <0.001) compared to PBC. BV/Nivo had significantly higher CR rate (67% vs 49%, p <0.001) and a trend towards higher ORR (86% vs 79%, p = 0.1) compared to PBC. BV had significantly lower ORR (62% vs 79%, p <0.001) and CR rate (34% vs 49%, p <0.001) compared to PBC. There was no difference in ORR and CR rate of PBC, Gem, CPI and Misc agents. Final ST prior to ASCT was PBC in 451, BBV in 76, BV/Nivo in 48, BV in 87, CPI in 24, Gem in 90 and Misc in 64. Table 1 lists K-M estimates of 2-year survival probabilities for different Final ST groups. Median follow up was 3 (range 0.1-13) years. BV/Nivo group had significantly higher proportion of patients with PRD and BD than PBC, no other differences in baseline characteristics were identified amongst ST groups (data not shown). BV/Nivo (HR: 0.1 (CI 95:0.02-0.4), p<0.01) and CPI (HR: 0.12 (CI 95:0.03-0.5), p<0.01) had significantly higher PFS than PBC. There was no significant difference in PFS between other ST groups (Figure 1a). Type of ST was not significantly associated with difference in OS (Figure 1b). 536 pts underwent ASCT in CR, 273 underwent ASCT in partial response (PR) and 31 underwent ASCT with progressive disease (PD). Pre-ASCT PR (HR 1.6 (CI 95:1.3-2.6), p<0.001) and PD (HR: 4.1 (CI 95: 2.5-6.8), p<0.001) predicted significantly lower PFS compared to CR (Figure 2a). OS was also significantly lower in pts with pre-ASCT PR (HR 1.7 (CI 95: 1.2-1.6), p<0.001) and PD (HR 5.3 (CI 95: 2.8-10), p<0.001) (Figure 2b). Higher number of pre-ASCT ST predicted lower PFS (HR 1.3 (CI 95: 1.1-1.6), p<0.001) and OS (HR 1.5 (CI 95: 1.2-1.8), p<0.001). In pts with pre-ASCT CR, all 36 who had pre-ASCT CR after BV/Nivo were alive and relapse free for follow up of 0.1-5 yrs. BV/Nivo was associated with significantly higher PFS (HR 0.1 (CI 95: 0.01-0.7), p <0.05) but not OS compared to PBC in this subgroup. Increasing number of pre-ASCT ST predicted worse PFS (HR 1.5 (CI 95: 1.2-2.0), p<0.01) and OS (HR 2.2 (CI 95: 1.4-3.4), p<0.001) in this subgroup as well. Conclusions: BV/Nivo has a higher CR rate and better post-ASCT PFS compared to conventional chemotherapy and can lead to durable remissions in pts with pre-ASCT CR. BBV had a higher response rate and similar post-ASCT survival to conventional chemotherapy. BV had lower response rates compared to chemotherapy. Novel ST such as BV/Nivo and BBV may be preferable to conventional chemotherapy in R/R cHL. Figure 1 Figure 1. Disclosures Spinner: Notable Labs: Honoraria. Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dorritie: SITC presentation: Honoraria; Genmab: Research Funding; University of Pittsburgh/UPMC Hillman Cancer Center: Current Employment; Janssen: Research Funding; F. Hoffman-La Roche Ltd: Research Funding; Juno/BMS: Research Funding; Kite, a Gilead Company: Research Funding; OncLive/Institutional Perspectives on Cancer presentation: Honoraria. Arai: Magenta Therapeutics: Research Funding. Maurer: Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Diefenbach: Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; IMab: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; AbbVie: Research Funding; IGM Biosciences: Research Funding; Incyte: Research Funding; Trillium: Research Funding; Gilead: Current equity holder in publicly-traded company; MEI: Consultancy, Research Funding. Nowakowski: Kyte Pharma: Consultancy; Ryvu Therapeutics: Consultancy; Selvita: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy; Bantham Pharmaceutical: Consultancy; Daiichi Sankyo: Consultancy; Zai Labolatory: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees.

Abstract Primary cutaneous diffuse large B‐cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved‐site radiation therapy (ISRT) is considered standard front‐line therapy. Over‐expression of PD‐L1/PD‐L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan–Meier method, we calculated progression‐free survival, duration of response, and overall survival in patients who received front‐line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R‐CHOP plus ISRT was 58 months (95% CI: 18–112) compared to 14 months (95% CI: 5–not reached; p = 0.04) in those treated with R‐CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4–not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4–26]. R‐CHOP with ISRT had a significantly longer median PFS compared to R‐CHOP without ISRT as front‐line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre‐treated patients was observed in this study.

SummaryFimepinostat (CUDC‐907), a first‐in‐class oral small‐molecule inhibitor of histone deacetylase and phosphatidylinositol 3‐kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high‐grade B‐cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/orMYCgene rearrangement/copy number gain (MYC‐altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end‐point of overall response (OR) rate for patients with MYC‐IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC‐altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC‐altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three‐protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC‐altered R/R DLBCL/HGBL treated with single‐agent fimepinostat. Combination therapies and/or biomarker‐based patient selection strategies may lead to higher response rates in future clinical trials.