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The single transmembrane domain (TMD) of the human thrombopoietin receptor (TpoR/myeloproliferative leukemia [MPL] protein), encoded by exon 10 of the MPL gene, is a hotspot for somatic mutations associated with myeloproliferative neoplasms (MPNs). Approximately 6% and 14% of JAK2 V617F− essential thrombocythemia and primary myelofibrosis patients, respectively, have “canonical” MPL exon 10 driver mutations W515L/K/R/A or S505N, which generate constitutively active receptors and consequent loss of Tpo dependence. Other “noncanonical” MPL exon 10 mutations have also been identified in patients, both alone and in combination with canonical mutations, but, in almost all cases, their functional consequences and relevance to disease are unknown. Here, we used a deep mutational scanning approach to evaluate all possible single amino acid substitutions in the human TpoR TMD for their ability to confer cytokine-independent growth in Ba/F3 cells. We identified all currently recognized driver mutations and 7 novel mutations that cause constitutive TpoR activation, and a much larger number of second-site mutations that enhance S505N-driven activation. We found examples of both of these categories in published and previously unpublished MPL exon 10 sequencing data from MPN patients, demonstrating that some, if not all, of the new mutations reported here represent likely drivers or modifiers of myeloproliferative disease.

The histone acetyltransferase HBO1 (MYST2, KAT7) is indispensable for postgastrulation development, histone H3 lysine 14 acetylation (H3K14Ac), and the expression of embryonic patterning genes. In this study, we report the role of HBO1 in regulating hematopoietic stem cell function in adult hematopoiesis. We used 2 complementary cre-recombinase transgenes to conditionally delete Hbo1 (Mx1-Cre and Rosa26-CreERT2). Hbo1-null mice became moribund due to hematopoietic failure with pancytopenia in the blood and bone marrow 2 to 6 weeks after Hbo1 deletion. Hbo1-deleted bone marrow cells failed to repopulate hemoablated recipients in competitive transplantation experiments. Hbo1 deletion caused a rapid loss of hematopoietic progenitors. The numbers of lineage-restricted progenitors for the erythroid, myeloid, B-, and T-cell lineages were reduced. Loss of HBO1 resulted in an abnormally high rate of recruitment of quiescent hematopoietic stem cells (HSCs) into the cell cycle. Cycling HSCs produced progenitors at the expense of self-renewal, which led to the exhaustion of the HSC pool. Mechanistically, genes important for HSC functions were downregulated in HSC-enriched cell populations after Hbo1 deletion, including genes essential for HSC quiescence and self-renewal, such as Mpl, Tek(Tie-2), Gfi1b, Egr1, Tal1(Scl), Gata2, Erg, Pbx1, Meis1, and Hox9, as well as genes important for multipotent progenitor cells and lineage-specific progenitor cells, such as Gata1. HBO1 was required for H3K14Ac through the genome and particularly at gene loci required for HSC quiescence and self-renewal. Our data indicate that HBO1 promotes the expression of a transcription factor network essential for HSC maintenance and self-renewal in adult hematopoiesis.

Introduction Chimeric antigen receptor (CAR) T cell therapy has been extremely efficacious in pediatric patients with multiply relapsed and/or refractory B-cell acute lymphoblastic leukemia (B-ALL) with overall remission rates of 81% by three months post-infusion (Maude et al., N Engl J Med, 2018), and achieved FDA approval for this indication. In order for the product to meet the standards of this approval for commercial release, both the leukapheresis and manufactured products must meet a variety of specific requirements, some of which are more stringent than those in these pivotal clinical trials. The Managed Access Program (MAP) provides access to tisagenlecleucel for patients with B-ALL or diffuse large B-cell lymphoma that is out of specification (OOS) for whom repeat leukapheresis is not feasible. Patients may also receive OOS tisagenlecleucel by applying for a single-patient Investigational New Drug (IND). Previous reports have shown no difference in efficacy or toxicity between patients receiving tisagenlecleucel that meets commercial release specifications and those receiving OOS tisagenlecleucel (Grupp, et al., Blood Abstr 614, 2019; Jaglowski, et al., Blood Abstr 627, 2019). This study seeks to evaluate outcomes in pediatric and young adult patients who received tisagenlecleucel via the MAP or a single-patient IND in our Pediatric Real World CAR Consortium (PRWCC). Methods Retrospective data were abstracted from the PRWCC database of patients with relapsed/refractory B-ALL from fifteen different US institutions who received tisagenlecleucel as an FDA-approved therapy outside the context of a clinical trial. Patients whose cellular product was obtained through the MAP (NCT03601442) or with single patient IND approval due having either a cryopreserved leukapheresis product and/or manufactured tisagenlecleucel that did not meet specifications for commercial release were categorized as MAP/IND and those whose product met all release criteria were categorized as standard of care (SOC). Results Among 185 total infused patients in our database, 24 (13%) received tisagenlecleucel either via the MAP (n=14) or a single patient IND (n=10). Baseline patient and disease characteristics were not significantly different for MAP/IND patients versus the SOC cohorts (Table 1). Median duration of follow-up post-CAR T cell infusion for these infused patients was 342.5 days (range 107-780) versus 318 days (range 6-863) for the SOC cohort (p=0.43). Reasons for products being OOS included cell viability 9 months prior (n=1), and determination of residual beads >50 beads/3x106cells (n=1). Overall survival at 6- and 12-months was 96% versus 83% and 85% versus 70% for the MAP/IND versus SOC, respectively. Event-free survival at 6- and 12-months was 65% versus 63% and 55% versus 51%, respectively. Probability of continued remission at 6- and 12-months among patients who achieved a complete remission (CR) at day 28 was 79% versus 75% and 66% versus 63% for the MAP/IND versus SOC, respectively (Figure 1). Comparing toxicities between patients in the MAP/IND versus SOC cohorts, cytokine release syndrome (CRS, any grade) occurred in 46% versus 61%, CRS (>grade 3) in 17% versus 19%, immune effector cell-associated neurotoxicity syndrome (ICANS) in 8% versus 22%, and infectious complications in 54% vs. 37%, respectively (p=ns for all). Conclusions In our retrospective cohort evaluating the use of tisagenlecleucel to treat pediatric and young adult patients with relapsed/refractory B-ALL in the real-world setting, neither the efficacy nor safety of tisagenlecleucel seem to be compromised by use of products OOS for commercial release. Larger studies are needed to further delineate specific cut-offs outside of which either efficacy and/or safety may truly be impacted. Disclosures Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees. Stefanski:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Verneris:Novartis: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Current equity holder in publicly-traded company; Bmogen: Consultancy, Current equity holder in publicly-traded company; Uptodate: Consultancy. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Brown:Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Qayed:Mesoblast: Consultancy; Novartis: Consultancy. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Satwani:Mesoblast: Consultancy; Takeda: Consultancy. Curran:Novartis: Consultancy, Research Funding; Celgene: Research Funding; Mesoblast: Consultancy. Mackall:Apricity Health: Consultancy, Current equity holder in private company; Lyell Immunopharma: Consultancy, Current equity holder in private company; BMS: Consultancy; Nektar Therapeutics: Consultancy; Allogene: Current equity holder in publicly-traded company; NeoImmune Tech: Consultancy. Laetsch:Novartis: Consultancy, Research Funding; Bayer: Research Funding; Pfizer: Research Funding; Cellectis: Consultancy.

Background: T cell lymphomas (TCL) have been known to exhibit epigenetic dysregulation and aberrant cell signaling. Tenalisib (RP6530), a highly selective PI3K δ/γ+SIK3 inhibitor has shown clinically promising activity as a single agent in TCL with a differentiated and favorable safety profile. In vitro studies in TCL cell lines showed increased apoptosis when tenalisib was combined with romidepsin (Rhizen data on file). A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics and efficacy in relapsed/refractory TCL (NCT03770000). Methods: This is a multi-center, open label, Phase I/II study in patients with T cell lymphoma (PTCL and CTCL). The Phase I is a 3+3 dose escalation study to determine the MTD/optimal dose. The Phase II is an expansion cohort at the MTD/optimal dose of the combination. Tenalisib was administered orally at doses of 400, 600 and 800 mg BID in combination with romidepsin (12 &14 mg/m2, Q3W). The objectives of the study are to establish safety, MTD/optimal dose, pharmacokinetics and anti-tumor activity of the combination. We report the dose escalation results and preliminary data from the expansion cohorts. Results: A total 15 patients were enrolled between July 24, 2019 and July 20, 2020. Baseline demographics are presented in Table 1. Patients had a median of 3 (range; 1-17) prior treatments and 11 (73%) were refractory to their last therapy. About 67% (6/9) of CTCL patients had prior mogamulizumab therapy. No DLT was reported in the dose escalation phase and Tenalisib 800 mg BID+ Romidepsin 14 mg/m2, Q3W was considered as the optimal dose for expansion cohorts. PK analysis showed linear and dose-dependent kinetics for tenalisib. Co-administration of romidepsin along with tenalisib did not significantly alter the mutual PK of either agents. Fifteen patients were assessed for safety. Most common treatment emergent adverse events of any grade were nausea (33%), thrombocytopenia (33%) and fatigue (27%). Related ≥ Grade 3 AEs were seen in 5 (33%) patients. These included thrombocytopenia (7%), atrial fibrillation (7%) and pyrexia (7%) which were related to romidepsin while anemia (7%) neutropenia (7%) and rash (7%) were considered related to the combination. There were no instances of transaminitis or colitis. None of the TEAEs led to study discontinuation. Patients from the dose escalation cohorts (n=9) were evaluated for response. Three patients (3/9) showed complete response (CR), 4 patients (4/9) showed stable disease (SD) while 2 patients (2/9) had progressive disease (PD). Out of the three responders, two were PTCL (AITL) patients, one of which is planned for transplantation, while the third patient was a CTCL (Sezary syndrome) patient who had progressed on prior mogamulizumab therapy. This patient showed rapid reduction of Sezary cell count after 2 cycles of treatment. Three patients (2 CR, 1 SD) are currently ongoing with a median duration of response being 9.0 (range; 7.6-10.5+) months. The expansion cohort has 6 patients and is currently enrolling. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising indicators of combined anti-tumour activity in patients with R/R TCL. The expansion cohort in CTCL and PTCL is currently underway to validate these encouraging early results. Updated results will be presented during the ASH meeting. Disclosures Iyer: Afffimed: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Target Oncology: Honoraria; Spectrum: Research Funding; Merck: Research Funding; CRISPR: Research Funding. Huen:Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin: Consultancy, Research Funding; Rhizen: Research Funding; Glaxo Smith Kline: Research Funding; Galderma: Research Funding; Miragen: Research Funding; Helsinn: Consultancy; Medivir: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuzel:Eselixis, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Health: Honoraria; Sanofi/Genzyme: Honoraria; Bioarray: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Marck: Membership on an entity's Board of Directors or advisory committees; Tyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Feldman:Viracta: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Cell Medica: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding. Reddy:KITE Pharma, Abbvie, BMS, Celgene: Consultancy; Genentech, BMS: Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.

Background: Acute Myeloid Leukemia (AML) and high-risk Myelodysplastic Syndrome (MDS) patients frequently receive antibiotics (ABX) for febrile neutropenia (prophylaxis or empirical treatment) or for suspected or documented bacterial infections. ABX affect the composition of the human intestinal microbiome and the resulting dysbiosis can have important consequences for patients including Clostridioides difficile infections (CDI). The reported cumulative incidence of CDI in patients with AML varies from 9 to 24% in the first 120 days following the start of induction chemotherapy and from 8 to 31% after allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). In patients undergoing allo-HSCT, acute Graft-versus-Host Disease (GvHD) and GvHD-related mortality are other important complications associated with intestinal dysbiosis, as shown in experimental studies in mice and retrospective analyses in humans. DAV132 is a microbiome protective therapy that can be administered concomitantly with oral or intravenous ABX. It has been primarily developed for adsorbing antibiotic residues in the distal ileum and colon in order to preserve the integrity of the gut microbiome, without impacting antimicrobial pharmacokinetics. Randomized clinical trials conducted to date, both in heathy volunteers and in patients, showed that DAV132 adsorbed residues of ABX in the colon and protected the intestinal microbiome from the dysbiosis induced by ABX while preserving their bioavailability. In addition, DAV132 was safely used in hospitalized patients receiving (multiple) concomitant drugs. Study Design and Methods: MICROCARE is a multicenter, randomized, placebo-controlled, parallel-arm phase 3 clinical trial. A total of 900 patients (randomized 1:1 to either DAV132 or placebo) are planned to be enrolled in approximately 80 study sites worldwide. The primary objective of this study is to evaluate the efficacy of DAV132 in preventing CDI in patients with newly diagnosed AML or high-risk MDS treated with intensive chemotherapy. In addition, the study aims to determine whether the protection of the intestinal microbiome with DAV132 can reduce the incidence of colonization with multidrug-resistant bacteria, bacteremia, and acute GvHD, and improve the long-term outcomes of transplanted patients. Randomization will be stratified by (i) site, and (ii) use of ABX within 30 days before inclusion and/or history of CDI. During the cycle of induction chemotherapy, DAV132 will be administered to patients every day until neutrophil recovery, regardless of the administration of ABX treatment. After neutrophil recovery and up to day 120, DAV132 will be administered every time an ABX treatment is given, for the length of the ABX treatment plus 2 days. The primary analysis of this study is the comparison of the time to CDI between DAV132 patients versus placebo patients up to 120 days after randomization. This will be analyzed using the cause-specific Cox proportional hazards model, whereby time to CDI is the outcome of interest, and mortality will be considered as competing event. In the primary outcome, a cause-specific Cox model will be used assuming that the impact of DAV132 on mortality is negligible; this will be confirmed in a secondary analysis. Secondary and exploratory endpoints include the rate of patients with ABX-associated diarrhea, the rate of patients with a gut colonization by resistant bacteria or a bloodstream infection, the diversity of the gut microbiome, the incidence of acute GvHD and overall survival. Two interim analyses will be performed at approximately 35 and 50 CDI events. Study status: Recruitment of patients in the study is starting in multiple countries in Europe. A first patient has been randomized in July 2021. Topics: Microbiome; CDI; GvHD; Dysbiosis; Antibiotics Disclosure: This work is supported by the IMI Joint Undertaking (JU) (grant 115523), Combatting Bacterial Resistance in Europe, with resources including financial contribution from the EU's Seventh Framework Programme and in-kind contributions from Da Volterra, a company part of the European Federation of Pharmaceutical Industries and Associations (EFPIA). Disclosures Vehreschild: 3M: Research Funding; Astellas Pharma: Consultancy, Research Funding, Speakers Bureau; Biontech: Research Funding; Da Volterra: Consultancy, Research Funding, Speakers Bureau; Evonik: Research Funding; Gilead Sciences: Consultancy, Research Funding, Speakers Bureau; Glycom: Research Funding; Immunic AG: Consultancy, Research Funding, Speakers Bureau; MaaT Pharma: Consultancy, Research Funding; Merck/MSD: Consultancy, Research Funding, Speakers Bureau; Organobalance: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Seres Therapeutics: Research Funding; Takeda Pharmaceutical: Research Funding; Alb Fils Kliniken GmbH: Consultancy, Speakers Bureau; Arderypharm: Consultancy, Speakers Bureau; Basilea: Consultancy, Speakers Bureau; Bio-Mérieux: Consultancy, Speakers Bureau; Farmak International Holding GmbH: Consultancy, Honoraria, Speakers Bureau; Ferring: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; SocraTec R&D GmbH: Consultancy, Speakers Bureau. Dane: Da Volterra: Consultancy. Mentré: Da Volterra: Consultancy. Burdet: Da Volterra: Consultancy; Mylan: Consultancy. Sablier-Gallis: Da Volterra: Current Employment, Current holder of individual stocks in a privately-held company. Andremont: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria. de Gunzburg: Da Volterra: Consultancy, Current holder of individual stocks in a privately-held company. Buffet: Da Volterra: Current Employment. Wilcox: Da Volterra: Consultancy, Research Funding. Cornely: Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis: Other: Grants or Contracts. Bonten: Merck/MSD: Research Funding; Janssen Vaccines: Consultancy, Speakers Bureau; OM Pharma: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding. Vitry: Da Volterra: Current Employment.

Background Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of T-cell non-Hodgkin's lymphomas with poor prognosis that are often refractory to treatment. Spleen tyrosine kinase (SYK) and Janus kinase (JAK) signaling pathways are important tumor survival mechanisms in PTCL. Cerdulatinib (ALXN2075) is an orally active, small molecule, reversible ATP-competitive dual inhibitor of SYK/JAK family members. The efficacy and safety of cerdulatinib monotherapy were investigated in a multicenter, single-arm Phase 2a dose-expansion study (NCT01994382) of patients with T- or B-cell malignancies; we report the final results from the PTCL cohort. Methods Eligible patients in the PTCL cohort were aged ≥18 years and had histologically confirmed PTCL with relapsed/refractory disease after ≥1 prior systemic therapy (prior brentuximab was required for CD30+ patients) and an Eastern Cooperative Oncology Group performance status ≤1. Patients received oral cerdulatinib 30 mg twice daily in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR) based on Lugano criteria. Secondary endpoints, including time to response (TTR), duration of response (DoR), and progression-free survival (PFS), were estimated. Efficacy was evaluated in patients who had ≥1 post-baseline scan. Safety was evaluated in all patients who received ≥1 dose. Results Overall, 220 patients (with various subtypes of B- and T-cell malignancies) were enrolled across 6 study cohorts. A total of 65 patients in the PTCL cohort received ≥1 dose of cerdulatinib and were included in this analysis: 63.1% male; median (range) age 65 (21-85) years; median (range) prior regimens 2 (1-10); 49.2% refractory to last treatment; 18 patients (27.7%) had prior stem cell transplant. Histologic types were angioimmunoblastic T-cell lymphoma/T follicular helper (AITL/TFH [N=29; 44.6%]); PTCL not otherwise specified (NOS [N=11; 16.9%]); and other rare T-cell leukemias and lymphomas (N=25; 38.5%; Table 1). Of 65 patients with PTCL, 58 were evaluable for efficacy (Table 1). ORR was 36.2% (95% CI 24.0-49.9%) for the overall PTCL cohort (12 complete responses [CRs]; 9 partial responses [PRs]; 14 stable disease [SD]). For the AITL/TFH subgroup (N=27), ORR was 51.9% (95% CI 31.9-71.3%) (10 CR; 4 PR; 3 SD). ORR (95% CI) in the safety population was 32.3% (21.2-45.1%) for PTCL overall (N=65) and 48.3% (29.4-67.5%) for AITL/TFH (N=29). Median (range) TTR for AITL/TFH was 1.9 (1.5-16.5) months (first scan at 2 months). Median (range) DoR for AITL/TFH was 12.9 (0.0-35.5) months with median (range) follow-up of 16.4 (0-35.5) months. PFS for the AITL/TFH subgroup was estimated to be median (range) 4.6 (0.6-37.4) months with median (range) follow-up of 22.4 (0.6-37.4) months. Further assessment is warranted. Median (range) time on treatment for all patients was 2.9 (0.2-37.9) months for PTCL overall and 3.3 (0.5-37.9) months for AITL/TFH, which appears comparable to time patients spent on their last prior therapy (median 2.2 and 3.0 months, respectively). The most common (≥5%) grade ≥3 treatment-emergent adverse events (TEAEs), excluding disease progression, were increased amylase (23.1%), anemia (20.0%), increased lipase (18.5%), neutropenia (12.3%), sepsis (9.2%), and diarrhea (7.7%). Increases in amylase and lipase were transient, reversible, and not associated with clinical pancreatitis. Adverse events were primary reasons for treatment discontinuation in 6 patients (9.2%) in the PTCL population (2 EBV reactivation, 1 West Nile viral infection, 1 sepsis, 1 infection, and 1 colitis). Conclusions Cerdulatinib demonstrated acceptable tolerability and clinical activity in PTCL. Complete and durable responses were observed in patients with the AITL/TFH subtype, including patients who had repeatedly relapsed and/or were refractory to their last treatment. These data provide proof of concept and a promising efficacy/safety profile for a first-in-class, dual SYK/JAK inhibitor in relapsed/refractory PTCL. Overall the benefit/risk profile of cerdulatinib treatment appears favorable in this population, with the exception of the PTCL NOS subgroup, in whom no responses were seen. This subtype-specific activity raises the potential for biomarker identification to optimize patient selection. Figure 1 Figure 1. Disclosures Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Ye: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Khodadoust: Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding. Munoz: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau. Hamlin: Incyte, Janssen, Molecular Templates: Research Funding; Alexion, AstraZeneca Rare Disease (formerly Portola Pharmaceuticals): Other: Study investigator, Research Funding; Kite, Karyopharm, Celgene: Membership on an entity's Board of Directors or advisory committees. Kim: Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding; Galderma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Soligenix: Research Funding; Eisai: Research Funding; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CRISPR: Research Funding; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Wilcox: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Patel: ModernaTX: Research Funding; EMD Serono: Membership on an entity's Board of Directors or advisory committees, Research Funding; Evelo Biosciences: Research Funding; GlaxoSmithKline: Research Funding; Bicycle Therapeutics: Research Funding; Mirati Therapeutics: Research Funding; Vigeo: Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Checkpoint Therapeutics: Research Funding; Effector Therapeutics: Research Funding; Forma Therapeutics: Research Funding; H3 Biomedicine: Research Funding; Boehringer Ingelheim: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus: Research Funding; Ignyta: Research Funding; Jacobio: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jounce Therapeutics: Research Funding; Klus Pharma: Research Funding; Kymab: Research Funding; Loxo Oncology: Research Funding; LSK Biopartners: Research Funding; Lycera: Research Funding; Placon Therapeutics: Research Funding; Portola Pharmaceuticals: Research Funding; Prelude Therapeutics: Research Funding; Qilu Puget Sound Biotherapeutics: Research Funding; Revolution Medicines: Research Funding; Ribon Therapeutics: Research Funding; Seven and Eight Biopharmaceuticals: Research Funding; Syndax: Research Funding; Synthorx: Research Funding; Stemline Therapeutics: Research Funding; Taiho: Research Funding; Takeda: Research Funding; Tesaro: Research Funding; Xencor: Research Funding; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Bayer: Membership on an entity's Board of Directors or advisory committees; ORIC Pharmaceuticals: Research Funding; Eli Lilly: Research Funding; Hengrui: Research Funding; Hutchinson MediPharma: Research Funding; Cyteir Therapeutics: Research Funding; Clovis: Research Funding; Calithera: Research Funding; AstraZeneca: Research Funding; Aileron Therapeutics: Research Funding; Artios Pharma: Research Funding; Gilead: Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Exelixis: Membership on an entity's Board of Directors or advisory committees; Vedanta: Research Funding; Curis: Research Funding; Ciclomed: Research Funding; TopAlliance: Research Funding; Macrogenics: Research Funding; Verastem: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioNTech: Research Funding; Millennium Pharmaceuticals: Research Funding; Merck: Research Funding; Mabspace: Research Funding; ADC Therapeutics: Research Funding; Acerta Pharma: Research Funding; Florida Cancer Specialists: Research Funding; Phoenix Molecular Designs: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Coffey: Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in publicly-traded company. Osman: Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in publicly-traded company. Holland: Alexion, AstraZeneca Rare Disease: Consultancy. Guzman: Alexion, AstraZeneca Rare Disease: Current Employment, Current equity holder in publicly-traded company. Smith: Alexion, AstraZeneca Rare Disease: Other: Study investigator; Celgene, Genetech, AbbVie: Consultancy. OffLabel Disclosure: Final safety and efficacy results from the PTCL cohort treated with cerdulatinib (ALXN2075); an orally active, small molecule, reversible ATP-competitive dual inhibitor of SYK/JAK family members.

Background: Most individuals diagnosed with indolent B-cell non-Hodgkin lymphoma (iB-NHL) should be expected to have a normal or near normal life span (Maurer et al., 2016). Thus, a major goal is identifying treatments that maintain efficacy while reducing toxicity and improve ease of administration. Window-of-opportunity studies are well-suited to evaluate the likely ceiling of activity of single agent therapies - assuming highest efficacy may be observed prior to emergence of resistance mechanisms or cumulative host toxicities. We hypothesized that oral ixazomib (Ix) would be safe and effective in untreated iB-NHL based on safety data in myeloma and efficacy data with the intravenous formulation (Assouline et al., 2014), and sought to evaluate it in the frontline setting both as a single agent (with a lead-in period) and together with rituximab (R). Methods: This single-arm, open-label phase II investigator-initiated trial (NCT 02339922) was conducted at the University of Washington / Fred Hutch Cancer Research Center / Seattle Cancer Care Alliance. Eligibility included an indication for treatment of iB-NHL per National Comprehensive Cancer Network guidelines, ECOG ≤ 2, and radiographically measurable disease. Prior standard systemic treatment of iB-NHL was permitted only for cases of mucosa-associated marginal zone lymphoma (MZL) relapsed after or refractory to antibiotics. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles. A single course of 4 weekly doses of R at 375 mg/m2 was added during the 7th cycle, closing the window period; Ix alone was continued until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response rate (ORR) after independent radiology review. Response assessment occurred at every 2 cycles using standard (Lugano) criteria. Results: Between February 2017 and January 2020 a total of 33 patients began treatment. The median age was 62 years (range 38 to 85) and 67% were men. Histologic subtypes included follicular lymphoma (FL, n = 20), MZL (n = 7), mantle cell lymphoma (MCL, n = 4), and small lymphocytic lymphoma (SLL, n = 2). The most common indications for therapy were bulky disease (42%) and symptoms due to lymphoma (27%). In cases of FL, 35% had > 6 cm tumor bulk and 20% had Follicular Lymphoma International Prognostic Index score ≥ 3. Median follow-up was 16.8 months (range 1.2 - 39.8). In the 6-month Ix-only window, the ORR was 24% for the entire cohort and 35% for FL [complete response (CR) rate 3% and 5%, respectively] (Figure 1). Reduction of disease was seen in 23 (70%), including 15 (75%) of FL, 4 (57%) of MZL, and 3 (75%) of MCL. Overall, the ORR was 45% and 60% for FL (CR rate 27% and 35%, respectively) as of June 1, 2020 (at which point 3 patients had yet to undergo evaluation post R). Progression free survival (PFS) at 2 years for all subjects was 62% and for those with FL was 69%; median PFS was not reached (Figure 2). For the 15 patients with objective response, the median time to response was 5.5 months (range 1.8 - 11.0) and the median duration of response was not reached (87% in remission at 2 yrs). Adverse events (AEs) > grade 3 deemed related to treatment were not observed and such grade 3 events occurred in 5 unique patients (15%). Serious AEs were recorded in 2 patients (6%). Most AEs were grade 1-2 and included nausea (58%, typically only for few a few hours after the weekly dose), diarrhea (39%), headache (30%), and vomiting (30%). Peripheral neuropathy (PN) was reported by 12% (motor PN in 9% and sensory PN in 3%); all cases were grade 1 except one case (3%) of grade 2 motor PN. Toxicity from Ix resulted in dose-holds in 21%, dose-reduction to 3 mg weekly in 9%, and discontinuation in 6% (one case of grade 3 hyponatremia and one case of grade 2 confusion). Conclusion: Once weekly oral Ix has a favorable safety profile and shows considerable activity in frontline treatment of iB-NHL, with the best results in FL. Combined with a single 4-week course of R, Ix can achieve durable disease control with very low toxicity in a majority of patients with FL, representing a convenient regimen amenable to remote management if indicated. This approach has the potential to support the overall strategy of lowering the burden of treatment while maintaining expected excellent outcomes in most patients with FL. Disclosures Graf: TG Therapeutics: Research Funding; BeiGene: Research Funding; MorphoSys: Consultancy; Acerta Pharma: Research Funding. Lynch:TG Therapeutics: Research Funding; Genentech: Research Funding; Juno Therpeutics: Research Funding; Incyte: Research Funding; Bayer: Research Funding; MorphoSys: Consultancy; Cyteir: Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Cowan:Bristol Myers Squibb: Research Funding; Sanofi: Consultancy; Cellectar: Consultancy; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Smith:Bristol Meyers Squibb: Research Funding; Incyte: Research Funding; Ayala: Research Funding; Bayer: Research Funding; AstraZeneca: Research Funding; Acerta Pharma BV: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Portola: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Consultancy; Millenium/Takeda: Consultancy; Beigene: Consultancy; Karyopharm: Consultancy; De Novo Biopharma: Research Funding; Genentech: Research Funding; Ignyta: Research Funding. Shadman:Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding. Godwin:Pfizer Inc.: Research Funding; Immunogen Inc.: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Kite/Gilead: Consultancy, Research Funding; Merck: Research Funding; Pfizer: Honoraria, Research Funding; Seattle Genetics: Current Employment, Current equity holder in publicly-traded company; Vanda Pharmaceuticals: Research Funding. Fromm:Merck: Research Funding. Gopal:Seattle Genetics; Janssen; IMab Bio; TG Therapeutics; Astra Zeneca; Merck; Gilead; ADC Therapeutics; Nurix; TG therapeutics, Cellectar; Actinium: Consultancy; Seattle Genetics; Janssen; Takeda; IgM Bio; IMab Bio; BMS; Astra Zeneca; Merck; Gilead: Research Funding; imab bio, takeda,astrazeneca,gilead: Research Funding; IgM bio, BMS, merck: Research Funding. OffLabel Disclosure: Ixazomib has not been approved for use in treating indolent B-NHL.

Background: Interleukin-2-Inducible T-Cell Kinase (ITK) is a Tec-family, non-receptor tyrosine kinase expressed in T-cells that plays a key role in T-cell receptor (TCR) signaling, which is required for development and differentiation of T-cells. In T-cell lymphoproliferative disorders, expression of the TCR and its downstream signaling components, including ITK, are maintained which suggests malignant T cells exploit this growth and survival pathway to their advantage. Antigen-presenting cells, abundant in the lymphoma microenvironment, also may provide antigen to drive TCR signaling through ITK. CPI-818 is a first-in-class, irreversible ITK inhibitor with selectivity for ITK. In preclinical studies, CPI-818 blocks TCR signaling in vitro and is efficacious in murine models and canines with T-cell lymphomas. We report results from the dose escalation portion of an ongoing phase 1/1b trial of CPI-818 in patients with relapsed/refractory T-cell lymphoma (CPI-818-001 study, NCT03952078). The trial is being conducted at sites in the United States, Australia, and South Korea. Methods: In dose-escalation, cohorts (3+3 design) enrolled patients with cutaneous and peripheral T-cell lymphoma who have progressed on, refractory to, relapsed, or intolerant to at least 2 standard therapies; age ≥ 18 years; ECOG status 0-1; and adequate organ function. CPI-818 was administered in ascending dose levels (100, 200, 400, 600mg BID) continuously for up to sixteen 21-day cycles, until progression or unacceptable toxicity. In dose expansion, PTCL-NOS and CTCL patients are receiving CPI-818 at a dose of 600 mg BID. The primary objectives of the study are to evaluate the safety and to establish the maximum tolerated dose (MTD) or the maximum administered dose of CPI-818. Safety events will be assessed according to the NCI-CTCAEv5. Secondary objectives include evaluating pharmacokinetics and efficacy as assessed by the investigator using standard response criteria at the end of every 3 cycles. ITK occupancy in peripheral blood T cells and tumor tissue as well as biomarkers associated with anti-tumor activity in tumor and blood samples are being evaluated. Results: In dose-escalation, sixteen patients were enrolled in four cohorts: 100 mg BID (n=4), 200 mg BID (n=3), 400 mg BID (n=5), and 600 mg BID (n=4). No dose-limiting toxicities were observed in any of these cohorts and the MTD was not reached. Treatment related adverse events (TRAEs) were reported in 9 (47.4%) patients and were all Grade 1-2 in severity. The most common (>1 patient) were fatigue (15.8%), nausea (10.5%), and rash (10.5%) and no infections were reported. By flow cytometry, no consistent changes in circulating non-malignant or total T cell number or phenotype were observed. Pharmacodynamic analysis revealed ITK engagement by CPI-818 in all cohorts when CPI-818 is dosed BID. With increasing dose, the trough ITK occupancy in both blood and tissue increased. At doses of 200 mg and greater, trough occupancies were >75%. Near complete ITK inhibition (98%) was achieved at 600 mg BID and therefore, this dose was selected as the expansion cohort dose and higher doses were not explored. Reduction in serum cytokines including IL2 (six of eight patients), IFNg (eight of eight patients), and TNFa (eight of eight patients) was observed 24hr post-dose in patients treated with doses of 400 and 600mg, but not at lower doses. In dose escalation, a total of four PTCL patients were enrolled at doses of 200 mg BID or greater. A confirmed complete response was achieved in one PTCL-NOS patient in the 200mg BID cohort. Among 7 CTCL patients enrolled, a Nodal CR, improved mSWAT and slowing of Sézary cell expansion were seen (Figure 1). Given the safety profile, the PK/PD findings, and the early signs of efficacy, PTCL-NOS and CTCL cohorts were expanded at 600mg BID. To date, two patients with PTCL-NOS and one patient with CTCL have been recently enrolled in expansion cohorts. Conclusion: The dose-escalation part of the CPI-818-001 trial demonstrated that the 100, 200, 400 and 600 mg BID doses are well tolerated. Clinical activity was observed in both PTCL-NOS and CTCL. Reduction of serum levels of canonical T cell cytokines is consistent with on-mechanism drug inhibition of inflammatory T cell pathways. Disease specific expansion cohorts for PTCL-NOS and CTCL are enrolling patients at a dose of 600 mg BID. Disclosures Khodadoust: Seattle Genetics: Consultancy; Kyowa Kirin: Consultancy. Feldman:Abbvie: Honoraria; Pharmacyclics: Honoraria, Other, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Bayer: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Kim:miRagen: Research Funding; Elorac: Research Funding; Neumedicine: Consultancy, Research Funding; Horizon Pharma: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kyowa-Kirin Pharma: Research Funding; Medivir: Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Merck: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Portola: Research Funding; Solingenix: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mehta-Shah:Karyopharm Therapeutics: Consultancy; Verastem: Research Funding; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Kyowa Hakko Kirin: Consultancy; Corvus: Research Funding; Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Genetech/Roche: Research Funding. Kim:Mundipharma: Research Funding; Donga: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Horwitz:ASTEX: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding; Beigene: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; GlaxoSmithKline: Consultancy. Buggy:Corvus Pharmaceuticals: Consultancy, Current Employment, Current equity holder in publicly-traded company. Hotson:Corvus Pharmaceuticals: Current Employment. Hill:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Munneke:Corvus Pharmaceuticals: Current Employment. Mahabhashyam:Corvus Pharmaceuticals: Current Employment. Miller:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Janc:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Mobasher:Corvus Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Introduction: Chimeric Antigen Receptor (CAR) T cell therapy targeting CD19 has shifted our treatment approach for relapsed and refractory (r/r) pediatric B cell acute lymphoblastic leukemia (ALL). The landmark ELIANA pediatric trial studying tisagenlecleucel, CD19-specific CAR T cells, demonstrated a complete response (CR) rate of 81% in 75 infused patients and 12 month overall survival (OS) and event-free survival (EFS) rates of 76% and 50% respectively. Cytokine release syndrome (CRS) and neurotoxicity rates of 77% and 40% were respectively reported. In August 2017, the FDA approved tisagenlecleucel for B-cell ALL that is refractory or in second or greater relapse in patients up to age 25. With CAR commercialization, institutions deliver tisagenlecleucel without the regulation of a clinical study and practices relating to CAR delivery and reporting remain heterogeneous. Here, we report real world clinical outcomes using commercially available tisagenlecleucel for pediatric r/r B-ALL. Methods and Results: Retrospective data were collected from PRWCC member institutions (n=15) and included 200 patients. This includes 15 (7.5%) patients not infused due to manufacturing failure (n=6), death from disease progression and/or toxicity (n=7), or physician discretion following disease remission from prior therapy(n=2). The remaining 185 patients (92.5%) were infused with tisagenlecleucel, including 87% (161) receiving standard-of-care CAR T cell products meeting manufacturing release criteria and 13% (24) receiving CD19-CAR T cells manufactured by Novartis and provided on the managed access program (NCT03601442; n=14) or with single-patient IND approval (n=10). At time of CAR T cell infusion, median age was 12 years (range 0-26) with 40% females and 60% males. Median duration of follow-up at time of analysis was 11.2 months (range 0.2-28.8). The CR rate at 1 month follow up was 79% (156/198) on an intent-to-treat basis and 85% (156/184) among evaluable infused patients. Of infused patients achieving morphologic CR with available testing, 97% (148/153) were negative for MRD by flow cytometry. Duration of remission at 6 and 12 months among patients who achieved CR was 75% and 63% respectively, with 35% (55/156) of responders experiencing relapse. At time of relapse, 41% (21/51) of evaluable patients had relapse with CD19- disease and 59% (30/51) had continued CD19 expression. OS and EFS rates were 85% and 64% at 6 months and 72% and 51% at 12 months, respectively. CRS and neurotoxicity of any grade were seen in 60% (111/184) and 22% (39/181) of evaluable patients with ≥ grade 3 CRS and neurotoxicity rates of 19% (35/184) and 7% (12/181) respectively. One grade 5 CRS and 1 grade 5 neurotoxicity (intracranial hemorrhage) were reported. Post infusion toxicity management included tocilizumab in 26% (47/184) and systemic steroids in 14% (25/184) of patients. Among 181 infused patients with documented disease burden, 51% (95) had high burden (HB) disease , as defined by >5% bone marrow lymphoblasts, peripheral blood lymphoblasts, CNS3 status or non-CNS extramedullary (EM) site of disease; 22% (40) had low burden (LB) disease, defined by detectable disease not meeting the HB criteria; and 25% (46) had no detectable disease (NDD) at time of last evaluation prior to CAR infusion. The morphologic CR rate was lower at day 28 in HB vs. LB and NDD (74% vs. 98% and 96%) and the OS and EFS were lower among patients with HB at 6 mo [OS; 75% (HB), 94%(LB), 98% (NDD), EFS; 50% (HB), 86% (LB), 75%(NDD), p Conclusions: This retrospective, multi-institutional analysis describes real world outcomes using tisagenlecleucel to treat pediatric r/r B-ALL. Early responses at 1 month and OS and EFS at 6 and 12 months are comparable to reported ELIANA trial outcomes. Safety is demonstrated in this cohort with lower rates or CRS and neurotoxicity, likely related to a lower disease burden cohort. Continued relapse and decrease in OS without evident plateau is seen following 6 months post-infusion warranting expanded follow up. Comparative analysis of outcomes in patient cohorts with varying disease burden demonstrate decreased CR, EFS and OS in patients with high disease burden as compared to patients with lower disease burden or no detectable disease at last evaluation prior to CAR infusion. Disclosures Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees. Stefanski:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Margossian:Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Verneris:Fate Therapeutics: Consultancy, Current equity holder in publicly-traded company; Novartis: Membership on an entity's Board of Directors or advisory committees; Bmogen: Consultancy, Current equity holder in publicly-traded company; Uptodate: Consultancy. Myers:Novartis: Consultancy, Honoraria, Other: ELIANA trial Steering Committee, Speakers Bureau. Brown:Jazz: Honoraria; Servier: Honoraria; Janssen: Consultancy; Novartis: Consultancy. Qayed:Novartis: Consultancy; Mesoblast: Consultancy. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Satwani:Takeda: Consultancy; Mesoblast: Consultancy. Curran:Novartis: Consultancy, Research Funding; Mesoblast: Consultancy; Celgene: Research Funding. Mackall:Lyell Immunopharma: Consultancy, Current equity holder in private company; Nektar Therapeutics: Consultancy; NeoImmune Tech: Consultancy; Apricity Health: Consultancy, Current equity holder in private company; BMS: Consultancy; Allogene: Current equity holder in publicly-traded company. Laetsch:Cellectis: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Consultancy, Research Funding.

Introduction Clinical decision support (CDS) technology has the potential to improve health outcomes by offering physicians an informational resource to support review and application of best pratices.1 The Multiple Myeloma Research Foundation (MMRF) and Intermountain Healthcare (IMH) conducted a study to assess the suitability of a single health system's data for a myeloma-specific CDS tool that visualizes treatment pathways, and to assess the effort needed to support a CDS program.2 This research is part of a longer-term effort to explore how CDS technology can help: - increase awareness of and apply treatment guidelines by visualizing pathways for specific MM patient cohorts - improve understanding of treatment variation within health systems - improve outcomes research by showing relationships between treatments and outcomes Methods IA12 data from the CoMMpass study3 was used to create a CDS tool prototype. These data were aggregated into state and transition maps to identify nodes and pathways with corresponding outcomes, including response, progression-free survival (PFS), and overall survival (OS). Intervening patient states were displayed using Sankey diagrams [Fig. 1]. We also tested if EMR data from a community health system (i.e., IMH) could support such visualization. The team designed a study protocol and obtained IRB approval. Inclusion criteria included patients with active MM between January 2016-June 2018; adult aged 18 years to 89 years at diagnosis of active or smoldering MM. An IMH-specific data dictionary was assessed for variable importance, quantity, and ease of acquisition. [Table 1]. IMH then manually abstracted prioritized structured (eg: labs) and non-structured (eg: notes) data for use in the tool. Results Ninety-six of an initial 146 patients meeting eligibility criteria had sufficient data usable for the study, reflecting 44 unique drug combinations across 9 lines of therapy. The tool was able to associate and visualize all patients and their clinical states and transitions to their outcomes. Clinical data was typically complete (99% of the time), including key clinician-derived data, such as ECOG scores (78%) and treatment response (99%). 569 person-hours were required to conduct the abstraction activity on 96 cases, averaging 5.9 hours/patient Discussion The IMH portion of the study supports the hypothesis that a community health system can provide sufficient high-quality information to power a CDS tool with priority features. Only 65% (96/146) of the initial study group had usable data because some patients had received partial care outside of the IMH integrated delivery network (IDN) leaving associated data inaccessible. Initial biostatistical analysis suggests that roughly 750-1000 complete patient records would be required for statistically significant outcomes research with granularly stratified cohorts. The MMRF is currently recruiting 5-7 additional large IDNs to obtain the patients to power more generalizable functionality. References 1 McKie PM, Kor DJ, Cook DA, Kessler ME, Carter RE, Wilson PM, et al. Computerized advisory decision support for cardiovascular diseases in primary care: a cluster randomized trial. Am J Med [Internet]. 2019 Dec 18 [cited 2020 Mar 5]. Available from: https://doi.org/10.1016/j.amjmed.2019.10.039 2 Garcelon N, Burgun A, Salomon R, Neuraz A. Electronic health records for the diagnosis of rare diseases. Kidney Int [Internet]. 2020 Jan 14 [cited 2020 Mar 5]. Available from: https://doi.org/10.1016/ j.kint.2019.11.037 3 Christofferson A, Nasser S, Aldrich J, Penaherrera D, Legendre C, Benard B, et al. Integrative analysis of the genomic landscape underlying multiple myeloma at diagnosis: an Mmrf Commpass analysis. Blood. 2017 Dec 7; 130 (Supplement 1): 326. Disclosures No relevant conflicts of interest to declare.

Background: In recent years, there has been a growing interest in telemedicine initiatives that maximize outcomes, reduce healthcare costs, and improve quality. The COVID-19 pandemic reduced healthcare access for many patients, including those undergoing chemotherapy, and thus accelerated these initiatives. We sought to evaluate the potential utility of telemedicine initiatives for lymphoma patients undergoing immunochemotherapy. Methods: To address this question, we conducted a retrospective review of adult lymphoma patients receiving R-CHOP +/- R, R-ICE, R-GEMOX, and R-DHAP at our institution in the last three years (2017-2019), and identified those for which dose modifications were required. Dose modifications were defined as a change in prescribed dose from the preceding cycle, or a change in the administered dose by 10% or greater. Laboratory results, patient history, and/or physical exam findings that informed dose modifications were retrospectively identified. Results: Of the 1,290 total treatment cycles identified in 301 unique patients, 1,102 cycles (85.4%) were R-CHOP +/- R, 105 (8.1%) were R-ICE, 71 (5.5%) were R-GEMOX, and 12 (0.9%) were R-DHAP. We found that 144 cycles (11.2%) were subject to dosing adjustments. The cohort of patients that received dose adjustments was comprised of 104 unique patients, of which 87 (60.4%) were male and 57 (39.6%) were female. Average age at diagnosis was 64 years old (Range: 22-91). Our cohort represented greater than 10 different lymphoma subtypes, most commonly Diffuse Large B-cell lymphoma (66.3%), Follicular lymphoma (14.5%), and Peripheral T-cell lymphomas (7.7%). We examined the basis for each dose adjustment by reviewing the clinical records from visits immediately preceding the dose adjusted cycle. Of the 144 dose adjustments, 11% of cycles contained dose increases due to a well-tolerated previous dose noted in the clinical assessment based on a combination of laboratory findings, interim history, and physical exam. The remaining 89% of adjustments (n=128) were dose reductions. The decision to dose reduce was most commonly informed by the clinical history (n=104, 81%). The clinical history was dichotomized into newly reported patient symptoms (69/104) or interim complications (35/104), usually infectious (n=26). Clinical assessments utilized laboratory findings as a rationale for dose reductions in 33/128 (26%) of cycles, most of which were secondary to myelosuppression (28/33 cycles). In contrast, only 7/128 dose reductions were based on physical exam findings alone, all of which were due to a change in patient body weight. As patients are routinely weighed immediately prior to chemotherapy administration, effectively no dose modifications (0/144) were exclusively based on abnormal physical exam finding during a pre-infusion assessment. Conclusions: The inability to perform a complete physical exam is a notable limitation of telemedicine initiatives. However, in an unselected group of lymphoma patients treated with immunochemotherapy, who subsequently had dose reductions to their regimens, we have found that all of the dose modifications were based on laboratory findings or the patient history, both of which are amenable to virtual visits. In stark contrast, no dose modifications were prompted by an abnormal physical exam finding alone. While further studies are needed, the data reviewed supports the implementation of telemedicine initiatives in lymphoma patients undergoing immunochemotherapy during the pandemic and potentially long term. Disclosures Phillips: Karyopharm: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bayer: Consultancy, Research Funding; BMS: Consultancy; Incyte: Consultancy, Other: travel expenses; Seattle Genetics: Consultancy; Cardinal Health: Consultancy.

Introduction Ibrutinib was FDA approved for relapsed or refractory (R/R) marginal zone lymphoma (MZL) based on a phase II clinical trial that showed an overall response rate of 48% (Noy et al, Blood 2017). However, factors associated with response to ibrutinib in R/R MZL and outcomes of patients after progression on ibrutinib are unknown. Given the poor survival in other B-cell lymphomas such as mantle cell lymphoma (MCL) after progression on ibrutinib (Martin P et al, Blood 2016), we sought to evaluate clinicopathologic characteristics predictive of ibrutinib failure in R/R MZL, and describe outcomes of patients who experienced progression on ibrutinib therapy. Methods We performed a multicenter retrospective study of MZL patients treated at 19 US medical centers. Eligible patients were ≥ 18 years diagnosed with MZL from 2010-2019, who received ibrutinib for R/R MZL. Patients achieving a complete response (CR) or partial response (PR) with ibrutinib were considered ibrutinib responders, while those who had stable disease (SD) or progression of disease (PD) were classified as non-responders. The primary endpoint was to evaluate factors predictive of primary progression (PD) on ibrutinib. Secondary endpoints include evaluation of predictors of overall survival (OS) and progression-free survival (PFS) following ibrutinib therapy, assessment of outcomes based on the sequencing of ibrutinib therapy, and evaluation of outcomes following ibrutinib failure. PFS was defined as time from the start of ibrutinib therapy until lymphoma relapse/progression or death from any cause, censoring at last clinical assessment if no progression or death. OS was defined as time from the start of ibrutinib treatment until death or last follow-up. A multivariable Poisson regression analysis was performed to model ibrutinib progression on the clinicopathologic factors (see Table). To identify significant predictors for OS and PFS, we used a multivariable Cox model. Results 101 patients with R/R MZL received ibrutinib, of whom 99 had sufficient data for inclusion in the analysis. Among these patients, 63% (n=62) had CR/PR to ibrutinib (ibrutinib responders, CR=17, PR=45) and 37% (n=37) had no response (ibrutinib non-responders, SD=25, PD=12). The median duration of follow-up was 1.8 years (range=0.1-5.4 years) and 2 years (range=0.2-6.3 years) for ibrutinib responders and non-responders, respectively. Baseline characteristics of the R/R MZL patients stratified by ibrutinib response are shown in the Table. Among all the baseline factors examined for association with ibrutinib progression, only primary refractory disease (refractory to frontline therapy, RR=3.78, 95%CI=1.36-10.45, p=0.01) was predictive of a higher probability of primary progression on ibrutinib on multivariable analysis. The median OS was significantly better for responders (NR [not reached], 95%CI=3.2-NR) compared to non-responders (3.4 years, 95%CI=1.4-NR) (Figure 1A). Achieving CR/PR with ibrutinib (HR=0.22, 95%CI=0.09-0.52) and lack of complex cytogenetics (HR=0.22, 95%CI=0.08-0.59) were predictors of superior PFS. Similarly, ibrutinib response (HR=0.13, 95%CI=0.03-0.53) and lack of complex cytogenetics (HR=0.19, 95%CI=0.04-0.87) were predictors of better OS. There was no difference in PFS or OS based on the timing of ibrutinib administration (second vs third vs fourth line and beyond, Figure 1B and 1C). The median post ibrutinib relapse/progression OS (PROS) for patients who initially responded then progressed on ibrutinib (secondary progression, n=19) was 4 years (Figure 1D). The median PROS for patients who had no response to ibrutinib were stratified according to SD vs PD. The median PROS for those who had SD was NR and those with PD was 0.1 year (Figure 1E). Conclusion This is the largest series of R/R MZL patients treated with ibrutinib. A history of primary refractory disease was predictive of primary progression on ibrutinib, while the presence of complex cytogenetics was associated with inferior PFS and OS. In contrast to MCL, the outcomes of patients who progress on ibrutinib in R/R MZL are not poor except for the primary progression cohort (those with PD as the best response to ibrutinib). Improving therapeutic options for patients who experience PD with ibrutinib treatment represents an urgent unmet need and these patients should be prioritized for evaluation of novel therapeutic approaches. Figure Disclosures Epperla: Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Reddy:Genentech, BMS: Research Funding; KITE Pharma, Abbvie, BMS, Celgene: Consultancy. Caimi:Genentech: Research Funding; Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding. Greenwell:Lymphoma Research Foundation: Research Funding; Acrotech Biopharma LLC, Kyowa Kirin: Consultancy. Janakiram:Takeda, Fate, Nektar: Research Funding. Olszewski:Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Awan:Genentech: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy; Kite Pharma: Consultancy; Dava Oncology: Consultancy; Celgene: Consultancy; Blueprint medicines: Consultancy; Sunesis: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy. Barta:Monsanto: Consultancy; Atara: Honoraria; Seattle Genetics: Honoraria, Research Funding; Janssen: Honoraria; Pfizer: Honoraria. Grover:Genentech: Research Funding; Tessa: Consultancy. Bartlett:Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed Therapeutics: Research Funding; Acerta: Consultancy; BTG: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Merck: Research Funding; Forty Seven: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; ADC Therapeutics: Consultancy; Autolus: Research Funding; BMS/Celgene: Research Funding. Christian:Acerta: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Merck: Research Funding; Millenium: Research Funding; MorphoSys: Research Funding; F Hoffman-La Roche: Research Funding; Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AstraZenica: Membership on an entity's Board of Directors or advisory committees. Herrera:Pharmacyclics: Research Funding; Immune Design: Research Funding; AstraZeneca: Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Karyopharm: Consultancy.