Park, Jae H.

Abstract ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

Background: Autologous T cells engineered to express a chimeric antigen receptor (CAR) targeting the B-cell lineage antigen CD19 (CAR19) in patients with relapsed/refractory (r/r) aggressive B-cell lymphomas (BCL) and pre-B acute lymphoblastic leukemia (B-ALL) have resulted in transformative improvements in clinical outcomes. However, there remain significant limitations concerning autologous CAR19 T cell manufacturing, including dysfunctional starting material, lack of product consistency and purity following genetic engineering, manufacturing timelines that necessitate the administration of bridging therapy in patients with aggressive disease, and insufficient quantities of CAR19 T cells, especially in severely cytopenic patients, to allow for more than single-dose administration routinely. The ability to consistently administer more than a single dose of CAR19 T cells enables dosing schedules that may reduce the risk of potentially life-threatening toxicities such as cytokine release syndrome and neurotoxicity, while maintaining or improving the depth and durability of anti-tumor responses. FT819 is a first-of-kind, off-the-shelf CAR19 T cell product candidate derived from a clonal master engineered induced pluripotent stem cell (iPSC) line, which can be used as a renewable source for the mass production of off-the-shelf CAR T cells for broad patient access. FT819 is engineered with the following features designed to improve the safety and efficacy of CAR T cell therapy: a novel 1XX CAR signaling domain, which has been shown to extend T cell effector function without eliciting exhaustion; integration of the CAR transgene directly into the T cell receptor alpha constant (TRAC) locus, which has been shown to promote uniform CAR expression and enhanced T cell potency; and complete bi-allelic disruption of T cell receptor (TCR) expression for the prevention of graft-versus-host disease (GVHD). FT819 has demonstrated antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines comparable to that of donor-derived CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia (Mandal et al. 2020). The properties of FT819 and its ability to improve outcomes of patients with B-cell malignancies warrants further clinical investigation. Study Design and Methods: This study is a multicenter, Phase I clinical trial of FT819 in patients with r/r B-cell malignancies, including BCL, chronic lymphocytic leukemia (CLL), and B-ALL. The primary objective of the trial is to determine the recommended Phase II dose of FT819. Key secondary objectives include evaluation of FT819 safety and tolerability, anti-tumor activity, and pharmacokinetics (PK). Exploratory objectives include characterization of FT819 pharmacodynamics as assessed by peripheral blood biomarkers, and by phenotypic and genetic characterization of the tumor microenvironment from paired pre- and post-treatment tumor biopsies. The dose-escalation part of the trial utilizes a 3+3 dose-escalation design to identify the maximum tolerated dose for BCL, CLL, and B-ALL. The dose-expansion part of the trial is designed to further characterize the safety, efficacy, and PK of FT819 in multiple indications. Up to a maximum of 300 patients will be enrolled. The trial will test up to four FT819 dose levels ranging from 30 to 900 million cells. Three FT819 dosing regimens each will be tested for BCL, CLL, and B-ALL: Regimen A, FT819 administered as a single dose; Regimen A1, FT819 administered as a single dose in combination with interleukin (IL)-2; and Regimen B, FT819 administered as fractionated doses on Days 1, 3, and 5. Lympho-conditioning will consist of three consecutive days of fludarabine and cyclophosphamide administered prior to the first dose of FT819. Key inclusion criteria include r/r disease after standard approved therapies, documented CD19 expression, and adequate organ function. Key exclusion criteria include ongoing immunosuppression such as systemic GVHD therapy, prior allograft organ transplant, active central nervous system involvement of disease, and known allergy to FT819 components. The trial is expected to begin patient recruitment in 2020. Disclosures Park: Novartis: Consultancy; Fate Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Genentech/Roche: Research Funding; Kite: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; GSK: Consultancy; Autolus: Consultancy, Research Funding; Intellia: Consultancy; Minverva: Consultancy; Takeda: Consultancy, Research Funding; AstraZeneca: Consultancy; Servier: Consultancy, Research Funding; Allogene: Consultancy; Juno Therapeutics: Research Funding; Artiva: Membership on an entity's Board of Directors or advisory committees. Jain:Pfizer: Research Funding; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. McGuirk:Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Astellas: Research Funding; Pluristem Ltd: Research Funding; Novartis: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding. Diaz:Fate Therapeutics, Inc.: Current Employment. Valamehr:Fate Therapeutics, Inc: Current Employment, Current equity holder in publicly-traded company. Chu:Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Roche Holding AG: Current equity holder in publicly-traded company. Castro:Kite Pharma: Research Funding; Pharmacyclics: Research Funding; Fate Therapeutics: Research Funding. OffLabel Disclosure: Cyclophosphamide and fludarabine will be used as lympho-conditioning therapy prior to FT819 administration. IL-2 will be administered in order to promote the expansion and function of FT819 as a T-cell product.

Abstract Background: Older patients (pts) with AML unfit for intense induction chemotherapy have a poor prognosis with a 5 year survival of <10%. 225Ac-lintuzumab is composed of 225Ac linked to a humanized anti-CD33 monoclonal antibody. Data were previously presented on the initial 13 pts who received 2.0 µCi/kg/dose on Days 1 and 8 (ASH, 2017, Abstract 616). Although that dose resulted in a high response rate of 69%, there were 6 pts with Grade 4 thrombocytopenia lasting >6 weeks and 5 CRi patients did not reach an ANC of ≥ 500/µL. Therefore, the activity level was reduced to 1.5 µCi/kg/dose for further evaluation. Methods: This study enrolled older pts with untreated AML who were considered to be unfit for standard induction chemotherapy. Pts aged 60 to 74 years were required to have significant co-morbidities, while all pts ≥ 75 years were eligible. Other eligibility criteria included ECOG PS 0-2, CD33 expression on > 25% of blasts, and a peripheral blast count <200/µL within 10 days of the first dose to optimize targeting of bone marrow (BM) blasts. Hydroxyurea was used to lower peripheral blast counts. 1.5 µCi/kg of 225Ac-lin were administered IV on Days 1 and 8. G-CSF was given starting 10 days after the 2nd dose and spironolactone was given for up to 1 year to minimize the risk of radiation-induced nephrotoxicity. Pts were evaluated for the CD33 splicing polymorphism SNP rs12459419. Results: 18 pts were included in this prespecified Interim Analysis. An additional 9 pts were treated at this dose and will be included in an updated analysis at the ASH meeting. The median age of the 18 pts was 73.5 years (range 60-87) and median ECOG Performance Status was 1 (0 in 3 pts, 1 in 9 pts, & 6 in 2 pts). 11 pts had prior AHDs (6 MDS, 2 CMML, 2 NHL, 1 myelofibrosis), and 9 had prior treatment for AHDs. Of the pts with known cytogenetic and molecular genetic results, 1 had favorable-risk, 3 had intermediate-risk, and 5 had adverse-risk AML using NCCN guidelines. The median baseline BM blast % was 40.5% (range, 22-66%) with a median CD33 expression of 62% (range, 26-100%) of AML cells. Objective responses were seen in 4 pts (22%): 3 complete remissions with incomplete platelet count recovery (CRp) and 1 complete remission with incomplete hematologic recovery (CRi). Among the responders with known cytogenetics, 1 pt had adverse genetics and 1 had Intermediate-risk genetics.Of the pts with remission, 3 had CT genotype for the CD33 splicing polymorphism SNP rs12459419 (including 2 CRp) and 1 had CC genotype. 3 of the responders are in follow up at Days 59, 169 and 266 without further treatment. Myelosuppression was seen in all pts including Grade 4 thrombocytopenia with marrow aplasia for > 6 weeks after the first dose in 4 pts. 1 pt with prior MDS had pancytopenia for > 4 months. The 3 pts with CRp achieved an ANC ≥ 1000/µL at Days 28, 38, and 40 from the first dose of 225Ac-lin. The pt with CRi did not reach an ANC of 500/µL. Non hematologic Grade ≥3 Treatment-Emergent adverse events (AEs) that were at least possibly related were 4 patients with febrile neutropenia, as well as 1 patient each with fungal pneumonia, acute respiratory failure, pulmonary edema, chest pain, sepsis, gastric hemorrhage, generalized muscle weakness, atrial fibrillation with rapid ventricular response and typhilitis. No pts had an infusion-related reaction requiring dose interruption. Veno-occlusive disease did not occur. The 30-day mortality rate was 16.7% (1 cardiac arrest and 2 with multi organ failure). Conclusions: Preliminary data from this Interim Analysis of 225Ac-lin monotherapy in older AML pts unfit for intensive therapy indicate a lower rate of myelosuppression at 1.5 µCi/kg/dose but also a lower response rate than was seen at 2.0 µCi/kg/dose. Although the study met the prespecified response criteria for continuing enrollment, it will be closed to further accrual in recognition that targeted radiation, like other therapies, will likely have the best outcomes when used in combination with other therapies in pts with active AML. An extensive development program in AML, MDS, and multiple myeloma is planned. One study will utilize 225Ac-lin in combination with salvage chemotherapy and another with venetoclax. 225Ac-lin will be used as a single agent for AML postremission therapy. In addition, 225Ac-lin will be used as targeted conditioning prior to hematopoietic stem cell transplant in pts with MDS with a complex karyotype and as a conditioning agent prior to autologous transplant in MM. Table. Table. Disclosures Atallah: Jazz: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Abbvie: Consultancy; BMS: Consultancy. Orozco:Actinium Pharmaceuticals: Research Funding. Craig:Novartis: Research Funding; Actinium Pharmaceuticals: Research Funding; Celgene: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Finn:Ochsner Clinic Foundation: Employment. Perl:NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; Astellas: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Research Funding; Shire: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Roboz:Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Pfizer: Consultancy; Argenx: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Roche/Genentech: Consultancy; Sandoz: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Otsuka: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Celltrion: Consultancy. Tse:Brown Cancer Center, University of Louisville School of Medicine: Employment; Jazz: Consultancy; Amgen: Consultancy; Amgen: Honoraria; Amgen: Honoraria. Mawad:Swedish Cancer Institute: Employment. Rizzieri:Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Jurcic:Astellas: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Celgene: Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Genetech: Research Funding; Kura Oncology: Research Funding.

Abstract The prognosis of elderly patients (pts) with acute lymphoblastic leukemia (ALL) remains poor, and novel therapeutic approaches are clearly needed. CD19 is expressed on the majority of precursor-B ALLs and represents an attractive therapeutic target. The anti-CD19 bi-specific engager antibody blinatumomab has demonstrated significant activity in both relapsed/refractory ALL and minimal residual disease (MRD) positive ALL. Therefore, we evaluated blinatumomab as a single agent in the upfront treatment of newly diagnosed elderly pts with Philadelphia chromosome (Ph) negative B-lineage ALL to determine response rates and overall survival (OS). Methods: Pts were treated at National Clinical Trial Network sites from June 2015 to September 2017. The primary objective of the study was to estimate 3-year OS. An IND was approved by the FDA and the protocol was approved by a central institutional review board. Eligibility: age > 65 years, newly diagnosed Ph negative B-lineage ALL with adequate organ function and no evidence of central nervous system (CNS) disease. Pts received blinatumomab for induction at standard dosing for 1-2 cycles until attainment of complete response (CR) or CR with incomplete count recovery (CRi) (defined below). Pts then received 3 cycles of blinatumomab post-remission therapy followed by 18 months of maintenance POMP (prednisone, vincristine, 6-mercaptopurine, methotrexate). A total of 8 doses of intrathecal methotrexate were administered as CNS prophylaxis. Cytogenetic risk was ascribed by NCCN 2018 criteria and bone marrow samples were analyzed for the presence of the Ph-like signature. MRD was assessed centrally by 8 color flow cytometry pre-treatment, on Day 35 of induction cycle 1, and on Day 35 of re-induction (if applicable). Response was assessed at the completion of 1-2 cycles of blinatumomab. CR was defined as < 5% marrow blasts with no evidence of extramedullary disease and recovery of counts [absolute neutrophil count (ANC) > 1000/uL, platelets >100,000/uL]. CRi was defined the same as CR but ANC < 1000/ uL and/ or platelets ≤ 100,000/ uL. OS was measured from day of registration on trial until the date of death. Disease-free survival (DFS) was measured from the date the pt achieved CR/ CRi until relapse or death. Toxicities were graded according to NCI CTCAE version 4.0. Results: Of 31 pts enrolled, 29 were eligible. The median age was 75 years (range 66 - 84), 22 (76%) were male, median baseline white blood count was 3.7 x 103/uL (range 0.3 - 7,100), and median bone marrow blast count percentage was 86.5% (range 30-100). Three pts received hydroxyurea or steroids prior to treatment initiation. Cytogenetic risk at diagnosis was: poor (34% of pts; n=10), standard (55% of pts; n=16), good (3% of pts; n=1) and unknown (7% of pts, n=2). Testing for the Ph-like signature is being completed. The most common Grade 3-5 non-hematologic toxicities related to treatment during induction were hyperglycemia (14%), dyspnea (10%), febrile neutropenia (10%), hypertension (10%), and lung infection (7%). One pt developed Grade 3 cytokine release syndrome and 1 developed Grade 3 neurotoxicity. No pts died during the first 28 days of treatment. The overall response rate (CR + CRi) was 66% (all CRs). Thirteen of the 19 responders have available MRD data post-treatment. Of these, 12 pts (92%) achieved MRD negativity, all at Cycle 1 Day 35. One pt required 2 cycles of blinatumomab to achieve CR. One pt proceeded to allogeneic hematopoietic stem cell transplant. The median follow-up time is 1 year and median duration on trial is 170 days (6 pts are still on maintenance therapy). OS estimated by Kaplan Meier at 6 months is 79% (95% CI 58%-90%) and at 1 year is 65% (95% CI 43%-80%). DFS estimated at 6 months is 68% (95% CI 43%-84%) and at 1 year is 56% (95% CI 31%-75%). No baseline features including CD19 expression (by percentage or mean-fluorescent intensity) or presence of a CD19 negative subpopulation were associated with response. Conclusions: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses. Disclosures Advani: Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Consultancy; Glycomimetics: Consultancy. Wieduwilt:Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Park:Adaptive Biotechnologies: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Erba:Immunogen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Agios: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Jazz: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Agios: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; MacroGenics: Consultancy; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; MacroGenics: Consultancy; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Janssen: Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Amgen: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Juno: Research Funding; Jazz: Consultancy, Speakers Bureau.

Abstract BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

Key Points KMT2C mutations occur in 15% and 25% of patients with cHCL and vHCL, respectively, along with CCND3 and U2AF1 mutations each in 13% of vHCLs. NF1, NF2, N/KRAS, and IRS1 alterations contribute to clinical resistance to vemurafenib treatment in patients with cHCL.

Key Points High WBC is an independent predictor of early HD in APL.

AbstractHairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.