Rosenthal, Allison

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

7556 Background: The majority of R/R NHL progressions after CART involve pre-existing sites, suggesting a promising role for bridging radiotherapy (bRT). We assessed the local control rate of disease sites bridged with radiotherapy prior to CART and identified predictors of in-field recurrence. Methods: We retrospectively reviewed 35 patients with aggressive B-cell NHL who received bRT between leukapheresis and CART infusion between 2018 and 2021 at a multi-site single institution. bRT local control rate (LC), calculated based on the total number of irradiated sites, was defined from bRT end date. Progression-free survival (PFS) and overall-survival (OS) were defined from the date of CART infusion. In-field recurrence was defined as disease relapse occurring within the radiation planning target volume. Kaplan-Meier plots and cox regression modeling were used to estimate the desired output. Results: Median age of the cohort at time of CART infusion was 59 (range 19-73). The median equivalent 2 Gy dose (EQD2) administered was 23.3 Gy (range 4-41 Gy). The median time from end of bRT to CART infusion was 14 days (range 6-42). Five (14%) patients also received bridging chemotherapy with bRT. Among the 34 evaluable patients, 30 (88%) achieved an objective response (59% complete response and 29% partial response). At a median follow-up of 12 months, 1-year PFS was 48% and 1-year OS was 72%. No progression occurred beyond 240 days. On review of treatment plans and pre-treatment PET/CT scans, 59 sites were identified that received bRT prior to CART infusion. The median size and SUVmax of the irradiated sites were 8.7cm (range 1.5-22) and 13 (range 4-46), respectively. Of the 59 irradiated sites, 8 sites (13.6%) in 7 patients had in-field local recurrence, translating to 1-year LC of 84%. No in-field recurrence occurred beyond 180 days. Moreover, no local recurrence occurred in patients who received radiation to all known sites of active disease to EQD2> 30 Gy (n = 4 patients); these patients remained in remission except for 1 who experienced progression outside the bRT field. On univariate analysis, triple hit lymphoma (THL) (OR 22.8, 95% CI: 3.8-138.3; p < 0.001), tumor size (OR 1.25, 95% CI: 1.1-1.4; p < 0.001), specifically ≥ 9cm (OR 9.4, CI: 1.2-77.3; p = 0.036) and SUVmax (OR 1.1, CI: 1.02-1.15; p = 0.008), specifically ≥ 20 (OR 5.6, CI: 1.3-23.7; p = 0.018), were significantly associated with increased risk of in-field recurrence. On multivariate analysis, THL (OR 32.9, CI: 3.2-336.0; p = 0.03) and tumor size (OR 1.3, CI: 1.1-1.6; p = 0.01) retained significant association with in-field recurrence. Conclusions: Bridging radiotherapy prior to CART provides excellent and durable in-field local control for R/R B-cell NHL. Patients with triple hit histology and bulky disease are likely at higher risk of in-field recurrence and may benefit from higher doses of bRT.

Abstract Multiple clinical trials have assessed de-escalation strategies from combined modality therapy (CMT) to chemotherapy-alone for the treatment of early-stage classical Hodgkin lymphoma (cHL), confirming similar outcomes. The application of these data to the real-world is limited, however. We conducted a retrospective, multicenter cohort study comparing CMT vs chemotherapy-alone in patients with early-stage cHL (stage IA-IIB) treated between January 2010 and December 2020. Positron emission tomography (PET) scans after chemotherapy cycle 2 (PET2) were independently reviewed by a nuclear radiologist (Deauville score ≥4, positive; ≤3, negative). Patient outcomes were compared by using an intention-to-treat analysis. Among 125 patients (CMT, n = 63; chemotherapy-alone, n = 62) with a median follow-up of 59.8 months (95% CI, 48.6-71.0), no differences in overall survival were observed (5-year overall survival, CMT 98.0% vs chemotherapy-alone 95.1%; log-rank test, P = .38). However, there was reduced progression-free survival (PFS) with chemotherapy-alone among all patients (2-year PFS, CMT 95.1% vs chemotherapy-alone 75.3%; log-rank test, P = .005) and in those with bulky (n = 43; log-rank test, P &lt; .001), unfavorable (n = 81; log-rank test, P = .002), or PET2-positive (n = 15; log-rank test, P = .02) disease. No significant differences in PFS were seen for patients with non-bulky (log-rank test, P = .35), favorable (log-rank test, P = .62), or PET2-negative (log-rank test, P = .19) disease. Based on our real-world experience, CMT seems beneficial for patients with early-stage cHL, especially those with PET2-positive and unfavorable disease. Chemotherapy-alone regimens can lead to comparable outcomes for patients with favorable, non-bulky, or PET2-negative disease. We conclude that although results seen in clinical trials are replicated in certain patient subgroups, other subgroups not fitting trial criteria do poorly when radiotherapy is excluded.

AbstractCutaneous T-cell lymphomas (CTCLs) are a spectrum of diseases with varied clinical courses caused by malignant clonal proliferation of skin-tropic T cells. Most patients have an indolent disease course managed with skin-directed therapies. In contrast, others, especially in advanced stages of disease or with specific forms, have aggressive progression and poor median survival. Sézary syndrome (SS), a leukemic variant of CTCL, lacks highly consistent phenotypic and genetic markers that may be leveraged to prevent the delay in diagnosis experienced by most patients with CTCL and could be useful for optimal treatment selection. Using single-cell mRNA and T-cell receptor sequencing of peripheral blood immune cells in SS, we extensively mapped the transcriptomic variations of nearly 50 000 T cells of both malignant and nonmalignant origins. We identified potential diverging SS cell populations, including quiescent and proliferative populations shared across multiple patients. In particular, the expression of AIRE was the most highly upregulated gene in our analysis, and AIRE protein expression could be observed over a variety of CTCLs. Furthermore, within a single patient, we were able to characterize differences in cell populations by comparing malignant T cells over the course of treatment with histone deacetylase inhibition and photopheresis. New cellular clusters after progression of the therapy notably exhibited increased expression of the transcriptional factor FOXP3, a master regulator of regulatory T-cell function, raising the potential implication of an evolving mechanism of immune evasion.

Abstract Polatuzumab vedotin (PV) is an antibody–drug conjugate targeting CD79b that is approved for patients with relapsed/refractory large B-cell lymphoma (LBCL). Patients who relapse after chimeric antigen receptor (CAR) T-cell therapy were not included in the registration study, and reports of PV use after CAR T cells are limited. This multicenter retrospective analysis included patients with LBCL who relapsed or progressed after CAR T-cell therapy and subsequently received PV with or without rituximab and bendamustine between July 2019 and May 2021. Response to treatment and progression were assessed based on the 2014 Lugano criteria. Fifty-seven patients were included in the study: 18 (32%) patients were primary refractory to CAR T-cell therapy, and 34 (60%) patients received PV-based therapy immediately after CAR T-cell therapy. PV was combined with rituximab in 54 (95%) patients and administered with bendamustine in 35 (61%) patients. A response was achieved in 25 (44%) patients, including complete remission in 8 (14%). No significant association between baseline characteristics and response was observed. After a median follow-up of 47 weeks (95% confidence interval [CI], 40-54), 46 (81%) patients had disease progression or died, and the median progression-free survival was 10 weeks (95% CI, 5-15). On a multivariate analysis, bone marrow involvement (hazard ratio, 5.2; 95% CI, 1.8-15; P = .003) and elevated lactate dehydrogenase levels (hazard ratio, 5.0; 95% CI, 1.4-16; P = .01) were associated with shorter progression-free survival. Studies aimed at better characterizing the intrinsic mechanism of resistance and identifying optimal consolidation strategies for these patients are warranted.

Primary effusion lymphoma (PEL) is a rare, aggressive B-cell lymphoma that usually localizes to serous body cavities to subsequently form effusions in the absence of a discrete mass. Although some tumors can develop in extracavitary locations, the areas most often affected include the peritoneum, pleural space, and the pericardium. PEL is associated with the presence of human herpesvirus 8 (HHV8), also called the Kaposi sarcoma-associated herpesvirus (KSHV), with some variability in transformation potential suggested by frequent coinfection with the Epstein-Barr virus (EBV) (~80%), although the nature of the oncogenesis is unclear. Most patients suffering with this disease are to some degree immunocompromised (e.g., Human immunodeficiency virus (HIV) infection or post-solid organ transplantation) and, even with aggressive treatment, prognosis remains poor. There is no definitive guideline for the treatment of PEL, although CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone) are frequently prescribed and, given the rarity of this disease, therapeutic focus is being redirected to personalized and targeted approaches in the experimental realm. Current clinical trials include the combination of lenalidomide and rituximab into the EPOCH regimen and the treatment of individuals with relapsed/refractory EBV-associated disease with tabelecleucel.

Abstract Introduction. About 60% of patients with large B-cell lymphoma (LBCL) relapse after standard of care (SOC) anti-CD19 autologous chimeric antigen receptor (CAR) T-cell therapy, CD19 downregulation representing a major mechanism of resistance. Therefore, agents able to target B-cell antigens other than CD19 could be clinically effective for these patients. Polatuzumab vedotin (PV) is an antibody-drug conjugate targeting CD79b, and approved by the FDA in combination with bendamustine and rituximab for patients with relapsed or refractory (r/r) LBCL. Patients who relapsed after CAR T-cell therapy were not included in the registration study, and reports of PV use after CAR T-cells in real world practice are very limited. Methods. This is a multi-center retrospective analysis of patients with LBCL who relapsed after SOC CAR T-cell therapy and subsequently received SOC PV with or without rituximab and bendamustine between 07/2019 and 04/2021. PV was given at the standard dose of 1.8 mg/kg IV every 3 weeks in all patients (except for one patient, who received 1.4 mg/Kg). Response to treatment and progression were defined according to 2014 Lugano criteria. Survival curves were calculated using Kaplan-Meier estimates, and were compared between subgroups using the log-rank test. Cox regression was used for multivariate analysis (MVA). Results. Fifty-four patients were included in the study: median age was 59 (range, 22-79 years), 38 (70%) were male, and 30 (56%) had an internal prognostic index score &gt; 3. Median number of systemic therapies before CAR T-cell therapy was 2 (range, 2-6), 16 (30%) patients previously had autologous stem cell transplant (SCT), and 2 (4%) had allogeneic SCT. Sixteen (30%) patients were primary refractory to CAR T-cell therapy, and median time from CAR T-cell therapy to PV was 5 months (range, 1-40 months). CD19 status at time of relapse after CAR T-cell therapy was assessed by immunohistochemistry and/or flow cytometry in 41 patients, and positive in 34 (83%); CD79b status was assessed in 14 patients, and positive in all cases (100%). Thirty-two (59%) patients received PV-based therapy immediately after CAR T cell therapy, while 22 (41%) had intervening treatments (median 1, range 1-5). At time of PV initiation, median absolute neutrophil count was 2.9 (range 0.5-19 X10 9/L), median platelet count was 87 X10 9/L (range 15-437 X10 9/L), median serum creatinine was 0.9 mg/dL (range 0.4-22 mg/dL), and 44 (81%) patients had elevated serum lactate dehydrogenase (LDH). The median number of PV cycles was 2 (range, 1-16): PV was combined with rituximab in 51 (94%) patients, and administered with bendamustine in 33 (61%). A response was achieved in 24 (45%) patients, including complete remission (CR) in 8 (14%) patients and partial remission in 16 (30%)(Figure A), with a median duration of response of 11 weeks (95%CI, 5-17 weeks). No significant association between baseline characteristics and response was observed. To date, 49 (91%) patients stopped PV: 38 (70%) due to progression, 7 (13%) because of CR/patient decision, 3 (6%) to proceed to allogeneic SCT, and 1 (2%) to proceed to an immunotherapy clinical trial (despite absence of progression). No patients stopped therapy because of toxicity. After a median follow up of 45 weeks (95% CI, 20-70 weeks), 44 (81%) patients progressed/died, and median PFS was 9 weeks (95% CI, 4-14 weeks). To date, 34 (63%) died, and median OS was 16 weeks (95% CI, 13-19 weeks)(Figure B). Causes of death included progression in 31 patients and transplant-related complications in 3. On univariate analysis, a shorter median progression-free survival (PFS) was observed for patients with bone marrow (BM) involvement (3 vs 10 weeks, p=0.002), prior central nervous system involvement (4 vs 10 weeks, p=0.02), and elevated LDH (6 months vs not reached, p=0.004). On MVA, the association was maintained only for BM involvement (hazard ratio [HR] 4.8; 95% confidence interval [CI] 1.6-12.5, p=0.004) and elevated LDH (HR 5; 1.4-16.7, p=0.01)(Figure C). Discussion. PV is safe and effective, but has short duration of response in r/r LBCL after anti-CD19 CAR T-cell therapy, except for patients with normal LDH. Studies aimed at better characterizing intrinsic mechanism of resistance, including upregulation of BCL2 family proteins, to favor the development of more effective PV-based combination strategies for these patients, are warranted. Figure 1 Figure 1. Disclosures Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. Kamdar: Celgene (BMS): Consultancy; Adaptive Biotechnologies: Consultancy; Genentech: Research Funding; Kite: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Genetech: Other; TG Therapeutics: Research Funding; SeaGen: Speakers Bureau; Celgene: Other; KaryoPharm: Consultancy; AbbVie: Consultancy. Hess: ADC Therapeutics: Consultancy; BMS: Speakers Bureau. Neelapu: Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Lin: Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Gamida Cell: Consultancy; Sorrento: Consultancy; Legend: Consultancy; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy.

Abstract BACKGROUND: Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with variable clinical outcomes. Commonly used risk stratification tools (Ki67 IHC, MIPI) in newly diagnosed MCL are not frequently used when selecting therapy, resulting in treatment choice being dictated by age and co-morbidities rather than disease biology. The MCL35 risk score was developed as a more reliable measure of proliferation and has been shown to be prognostic and can risk stratify younger transplant eligible MCL patients into three groups with significantly different overall survival (OS; Scott et al. 2017; Holte et al. 2018) but has not been evaluated in older transplant ineligible patients. We report results evaluating the prognostic value of the MCL35 assay in older MCL patients (≥65) treated with frontline bendamustine/rituximab (BR). METHODS: Archived tissue samples from 119 patients age ≥65 years treated with BR from collaborating Lymphoma/Leukemia Molecular Profiling Project (LLMPP) sites and the LEO/MER cohort were collected and analyzed using the MCL35 assay and stratified into three distinct risk groups (low, standard, and high risk). Association between MCL35 proliferation scores and OS were estimated by the Kaplan-Meier method and hazard ratios were calculated. Associations between Ki67, s-MIPI, p53 IHC status, morphology and OS were also evaluated. RESULTS: The MCL35 assay was run on tissue samples from 119 patients. Median patient age was 74 (range 65-93) and 69.5% were male. Ki67 was &lt;30% in 29 patients (24%) and ≥30% in 90 patients (76%). Simplified MIPI (s-MIPI) score was 0-3 in 21 patients (24%), 4-5 in 42 patients (48%) and ≥6 in 25 patients (28%). Thirty-one did not have sufficient data to calculate a s-MIPI score. MCL35 was low risk in 51 patients (43%), standard risk in 39 patients (33%) and high risk in 29 patients (24%). Eleven patients had blastic morphology, 7 had pleomorphic morphology and the remainder were classic morphology (n=56). Of 57 samples with p53 IHC staining 7 (12.3%) were positive. At a median follow up of 33.4 months, 82 patients were alive and 35 had died. Patients with high risk MCL35 score had inferior OS compared to low risk (HR 2.27, 95% CI: 1.03-5.00; p=0.042) while standard risk was not statistically significant compared to low risk (HR 0.87, 95% CI: 0.37-2.0; p=0.740)(Figure 1). Ki67 IHC using a cutoff of ≥ 30% and 10%-29% was not significantly associated with OS compared to Ki67 &lt;10% ( Ki67 ≥ 30% vs. Ki67 &lt; 10%, HR 0.87, 95% CI: 0.12-6.41; p=0.892, Ki67 ≥ 10%-29% vs. Ki67 &lt; 10%, HR 0.32, 95% CI: 0.04-2.83; p=0.303), however high s-MIPI score (≥6) (s-MIPI ≥6 vs. s-MIPI 0-3, HR 3.86, 95% CI 1.20-12.5; p=0.024) and positive p53 IHC (HR: 9.51, 3.26-27.7; p &lt;0.001) were both associated with poor OS. Eighteen cases were blastic/pleomorphic by morphology, 12 of which were in the high-risk group by MCL35, and this subset also had worse survival than classic MCL (p=0.0052). CONCLUSIONS: These results suggest high risk MCL35 score is a prognostic biomarker of poor OS in patients &gt;65 with MCL treated with BR. Conversely, Ki67 was not significantly associated with OS in these patients. Additional clinical validation using a larger sample size from the E1411 study is planned. If similar results are found, the MCL35 assay in combination with s-MIPI and p53 status may have utility in stratifying patients into risk adapted treatment arms in future prospective clinical trial designs. Figure 1 Figure 1. Disclosures Maurer: BMS: Research Funding; Genentech: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Villa: Janssen: Honoraria; Gilead: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Seattle Genetics: Honoraria; Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; NanoString Technologies: Honoraria. 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. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding. Raess: Scopio Labs: Research Funding. Scott: Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling.; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Rich/Genentech: Research Funding; Janssen: Consultancy, Research Funding; Incyte: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy. Rimsza: NanoString Technologies: Other: Fee-for-service contract.

Abstract Introduction: Novel genetic classifications of diffuse large B-cell lymphoma (DLBCL) highlight the molecular complexity beyond cell of origin and provide new therapeutic implications. Next generation trials may incorporate novel agents for different genetic subtypes based on the pathogenesis mechanisms. For example, with the LymphGen classification, the MCD, BN2, ST2, and EZB subtypes are predicted to be susceptive to PI3K/mTOR targeting (Wright 2020). However, PI3K inhibitors have not been tested in the frontline, although data on the mTOR inhibitor everolimus were encouraging (Alliance 1085). We launched a phase 1/1b trial (NCT04323956) to investigate the feasibility of combining a novel PI3K inhibitor parsaclisib with standard R-CHOP immunochemotherapy and to seek an efficacy signal. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) expression of either Myc (≥40%) or Bcl2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, regardless of morphology, was also eligible. All patients received parsaclisib plus R-CHOP. Phase 1 followed a 3+3 design and the primary endpoint was maximum tolerated dose (MTD) of parsaclisib. Dose levels tested were level 1 (20 mg QD, d1-10; starting level) and level 2 (20 mg QD, d1-14). MTD was defined as the dose level below the lowest dose that induced dose limiting toxicity (DLT) in at least one-third of patients. The primary endpoint in phase 1b is complete response (CR) rate by PET. Results: From July 2020 to June 2021, 15 patients were enrolled, 9 in phase 1 and 6 in phase 1b. The median age at diagnosis was 56 years (range 20-79), and 7 (47%) were female. One patient (7%) had ECOG PS ≥2, 7 (47%) had elevated LDH, 7 (47%) had &gt;1 extranodal site, 13 (87%) had stage III/IV, and 7 (47%) had high-intermediate or high risk International Prognostic Index. Pathology was DLBCL in 13 patients (2 with concurrent follicular lymphoma) and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements in 2 patients. Four (27%) had non-GCB subtype, 7 (47%) had Myc or Bcl2 single expression, 8 (53%) had Myc/Bcl2 double expression, and 5 (33%) had MYC rearrangement (2 with concurrent BCL2 and/or BCL6 rearrangements). In phase 1, 3 patients were enrolled at dose level 1 and 6 patients were enrolled at dose level 2. No DLT was observed. Therefore, MTD was not reached, and dose level 2 was selected for phase 1b dose expansion. Six patients were enrolled in phase 1b to date. At the data cutoff date of 7/22/2021, 8 patients completed all 6 cycles of treatment, 1 competed 5 cycles, 3 completed 3 cycles, 2 completed 2 cycles, and 1 completed 1 cycle. Treatment-related adverse events (AE) are summarized in Table 1. The most common hematological AE included lymphopenia (60%), anemia (53%), neutropenia (53%), and thrombocytopenia (27%), and the most common non-hematological AE included nausea (67%), alopecia (40%), constipation (33%), fatigue (33%), dyspepsia (20%), and peripheral sensory neuropathy (20%). The most common grade 3 or 4 AE included lymphopenia (47%), neutropenia (33%), and anemia (13%). One 80-year-old female required parsaclisib dose reduction in cycle 3 and subsequent parsaclisib discontinuation as well as cyclophosphamide and doxorubicin dose reductions due to febrile neutropenia (no source of infection was identified). No other patients required dose reductions. The median follow-up was 3.7 months (range 0.8-10.7). Thirteen patients were evaluable for interim response by PET. The objective response rate was 92%, with 8 (62%) CR and 4 (31%) partial response (PR). One (8%) patient progressed before cycle 2 following a transient clinical response (shrinking palpable mass). Among those who achieved an objective response at interim, 7 patients were evaluable for end of treatment response and all 7 maintained a response, with 6 (86%) CR and 1 (14%) PR. Conclusions: Parsaclisib and R-CHOP combination therapy was generally well tolerated, with no DLT observed in phase 1 and no major safety concerns in both phase 1 and the ongoing phase 1b expansion. The preliminary efficacy signal of objective response appears encouraging in a small cohort of high risk patients. Parsaclisib plus R-CHOP can be an experimental arm for future frontline DLBCL trials investigating genetic subtype-driven novel therapies. Figure 1 Figure 1. Disclosures Wang: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genentech: Research Funding; MorphoSys: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. King: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: 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: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. 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. OffLabel Disclosure: Parsaclisib is an investigational agent used in this clinical trial.