Lee, Sangmin

Abstract Introduction: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity toward transformation to acute myeloid leukemia. Type I JAK inhibitors (JAKi) are the only approved therapy and can provide symptom control and reduction of splenomegaly in eligible patients. However, JAKi do not significantly impact disease progression, and many patients are not eligible due to coexisting cytopenias. Patients with MF who have relapsed and/or are refractory (R/R) to JAKi have poor survival. Therefore, novel agents, moving beyond JAKi-based treatments, are urgently needed. CD123, also known as the interleukin-3 receptor alpha chain, is expressed on maturing myeloid cells and progenitors in MF, making it an attractive therapeutic target. Tagraxofusp (TAG, SL-401) is a CD123-targeted therapy which is FDA and EMA approved for the treatment of blastic plasmacytoid dendritic cell neoplasm. A phase 1/2 study of TAG monotherapy in patients with MF who were R/R to approved JAKi (NCT02268253) was initiated. Herein, we present updated safety and efficacy data. Methods: A 2-stage multicenter, phase 1/2 study enrolled patients with R/R MF. Patients in Stage 1 (dose escalation) received 7, 9, or 12 mcg/kg/day TAG intravenously on days 1-3, every 21 days (cycles 1-4), every 28 days (cycles 5-7), and every 42 days (for cycles 8 and beyond); 12 mcg/kg/day was given every 21 days (cycles 1-4), and every 28 days (cycles 5+) in Stage 2. Enrollment in Stage 2 (expansion) was restricted to patients who met the DIPSS-plus intermediate-2 or high-risk disease criteria, those who were R/R or intolerant to JAKi therapy, and those who were not eligible for immediate stem cell transplantation. Responses were assessed on the basis of the International Working Group MPN Research and Treatment/European LeukemiaNet (IWG-MRT/ELN) criteria (Tefferi et al. Blood 2013;122:1395-1398). Results: As of July 1, 2021, 39 patients with MF were treated. Median age was 70 years (range 54-87) and 46% were female. The baseline characteristics comprised thrombocytopenia (<100 × 10 9/L; 64%), including 36% with platelets <50 × 10 9/L; monocytosis (≥1.0 × 10 9/L; 21%), and splenomegaly (74%). Genomic assessments at study entry demonstrated molecular mutations in JAK2, CALR, MPL, and ASXL1 in 62%, 8%, 5%, and 23%, respectively; cytogenetic abnormalities were observed in 10 patients (4 patients: 20q-, 3 patients: 7/7q-, 2 patients: -5/5q-, 2 patients: 12p-, and 1 patient: 17q). Treatment-related adverse events are depicted in Table 1. The most common treatment-related adverse events (incidence ≥10%) included hypoalbuminemia (21%), headache, pyrexia, thrombocytopenia, and elevated alanine aminotransferase (15% each). Capillary leak syndrome (CLS) was reported in 3 patients, including 1 patient with grade 4; there was no grade 5 CLS. Stable disease was achieved in 21 patients (60%). In total, 12/24 patients (50%) with baseline splenomegaly achieved a spleen response (Table 2), 3/4 (75%) with concomitant monocytosis, and 13/24 (54%) with concomitant thrombocytopenia. Spleen responses were confirmed objectively by imaging, with the spleen volume reduction (SVR) thresholds for response set at 35%. Updated information on SVR will be reported at the time of presentation. Total Symptom Score (TSS) was reduced in 20/39 patients (51%), and 10/39 (26%) had reductions from baseline in both TSS and spleen size. Median overall survival was 29.2 months (95% CI 12.0-49.5; range 1-51 months). Conclusions: TAG monotherapy demonstrated clinical efficacy and a predictable and manageable safety profile in patients with MF characterized as high-risk, including those who are refractory to JAKi and those with associated monocytosis, thrombocytopenia, advanced disease, and high-risk genetic features. This phase 1/2 study confirms the safety and clinical efficacy of TAG administered as a monotherapy in a cohort of poor-prognosis patients with MF. Given the genomic and epigenomic complexity of MF, with the clonal heterogeneity and additional subclones, TAG is planned to be tested as part of a combination strategy in high-risk patients with MF who are either R/R, intolerant to, or who have had a prior suboptimal response to JAKi. Figure 1 Figure 1. Disclosures Yacoub: Agios: Membership on an entity's Board of Directors or advisory committees; Acceleron Pharma: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Wang: Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Lee: BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: FujiFilm: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Samus: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Geron: Research Funding; Bluebird Bio: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Onconova: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Regimmune: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Sangamo: Research Funding; Elevate: Research Funding; Biomed Valley Discoveries: Research Funding; Bio: Research Funding; Actuate: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Leukemia & Lymphoma Society: Research Funding; Ono-UK: Consultancy, Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Arog: Research Funding; Trovagene: Research Funding; Tolero: Research Funding; Takeda: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Pharma: Consultancy; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Taparia: Novartis: Consultancy. Verstovsek: Protagonist Therapeutics: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Ital Pharma: Research Funding; Blueprint Medicines Corp: Research Funding; Promedior: Research Funding; Genentech: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Brooks: Stemline Therapeutics: Current Employment. Mughal: Stemline: Current Employment, Current holder of stock options in a privately-held company; Oxford University Press, Informa: Other: financial benefit and/or patents . Pemmaraju: LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; Aptitude Health: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; CareDx, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Sager Strong Foundation: Other; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy.

Abstract Introduction CMML is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Current therapeutic options for patients (pts) with CMML are limited, leaving a significant unmet medical need. Pts classified to have the MPN subtype, compared with the MDS subtype, and those with high-risk genetic features tend to have a higher rate of transformation to acute myeloid leukemia (AML) and median survival of 2-3 years. The seminal observation of increased expression of CD123 (interleukin-3Rα) on leukemia stem cells and clonal plasmacytoid dendritic cells led to the clinical investigation of a novel CD123-targeted agent, tagraxofusp (TAG, SL-401), in CD123-positive hematologic malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), CMML, AML, and myelofibrosis. TAG demonstrated robust clinical activity in pts with BPDCN and is now approved in the US and EU for this indication. Data from an ongoing phase 1/2 study of TAG monotherapy for pts with relapsed/refractory (R/R) CMML (NCT02268253) also demonstrated clinical activity (Patnaik et al. J Clin Oncol 2019;37: abstr 7059). Herein, we present updated safety and efficacy results of this study in first-line (1L) high-risk and R/R pts. Methods A multicenter, multistage, phase 1/2 trial was designed initially to assess the safety and efficacy of TAG monotherapy in adult pts with R/R CMML (Stages 1 and 2), and subsequently expanded to include 1L high-risk and R/R pts (Stage 3A). Clinical responses were initially assessed by the International Working Group/MDS 2006 criteria, and subsequently amended to the MDS/MPN 2015 criteria. Splenomegaly was assessed by palpation in Stages 1 and 2, and by palpation and imaging in Stage 3A. TAG was administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days (d)1-3 every 21 d (cycles [C]1-4), 28 d (C5-7), and 42 d (C8 and beyond) in Stage 1, and at 12 mcg/kg (recommended phase 2 dose defined in Stage 1) every 21 d (C1-4) and 28 d (C5 and beyond) in Stages 2-3A. Results As of July 2021, 36 pts have been enrolled, comprising 20 pts with CMML-1 and 16 with CMML-2; median age is 69 years (range 42-81); 75% are male. Twenty-three (64%) pts had either high- or intermediate-risk genetics based on CPSS, GFM, MMM, or ELN risk-stratification systems. Prior therapies included HMA in 16 (43%) pts, allogeneic stem cell transplantation (allo-SCT) in 3 (8%), and other in 12 (32%); 7 (19%) pts were high-risk and treatment naive. Overall, 16 (44%) pts had baseline palpable splenomegaly, of whom 12 pts' spleen size was ≥5 cm below left costal margin. The most common (in ≥20% of pts, n=34) treatment-related adverse events (TRAEs) were hypoalbuminemia (26%), thrombocytopenia (24%), nausea (24%), and capillary leak syndrome (CLS, 21%; grade 2, n=4; grade 3, n=3). Grade ≥3 TRAEs were thrombocytopenia (21%), CLS (9%), anemia (9%), and nausea (3%). Discontinuation rate due to TRAEs was low (n=1). Overall, 4 of 36 (11%) pts achieved bone marrow morphologic complete responses (BMCRs), of whom 1 pt was bridged to allo-SCT; all 4 pts had splenomegaly at baseline. Noteworthy, 2 of the 4 BMCRs were observed in pts with high-risk genetic features. Fifteen (42%) pts with baseline splenomegaly had spleen responses; 9 (60%) pts had a ≥50% reduction in spleen size, including 5 (42%) with splenomegaly ≥5 cm at baseline. Median follow-up was 11 weeks (range 1-163 weeks). In the Stage 3A cohort, 2 high-risk 1L pts had BM partial remissions, with 1 also having clinical benefit. Three pts had a spleen volume reduction by MRI scans following C1 (range 7%-36%) and 1 pt had a reduction of 57% after C4. While on study, none of the 7 pts (2 transfusion dependent at baseline) have required blood or platelet transfusions. Updated results on Stage 3A, including total symptom scores, will be presented. Conclusions Ongoing results in pts with CMML demonstrate TAG monotherapy has significant clinical activity in 1L pts with high-risk disease as well as those with R/R disease. The responses were particularly notable in those with baseline splenomegaly. As Stage 3A of the trial continues, mutational correlates and BM PDCs are being assessed. TAG treatment is well-tolerated, with a manageable and predictable safety profile. Overall, the data suggest that TAG may offer a novel targeted approach for pts with CMML. Stage 3A of the trial continues. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Yacoub: Incyte: Consultancy, Honoraria, Speakers Bureau; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Gupta: Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Roche: Consultancy. Lee: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; FujiFilm: Research Funding; PrECOG: Research Funding; Karyopharm: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Actuate: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Celator: Research Funding; Daiichi-Sankyo: Research Funding; Arog: Research Funding; Forma: Research Funding; Samus: Research Funding; Deciphera: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Abbvie: Research Funding; Mateon: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: takeda: Research Funding; taiho: Honoraria; syros: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; abbvie: Research Funding; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; sanofi aventis: Honoraria; gamida: Honoraria; certara: Honoraria; servier: Honoraria; revolution medicine: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; OncLive: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Brooks: Stemline Therapeutics: Current Employment. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Pemmaraju: Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Bristol-Myers Squibb Co.: Consultancy; Sager Strong Foundation: Other; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ImmunoGen, Inc: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Pacylex Pharmaceuticals: Consultancy.

7058 Background: Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. CD123 is expressed on a variety of malignancies, including MF. CD123+ plasmacytoid dendritic cells (pDCs), in the MPN microenvironment, including chronic myelomonocytic leukemia and MF, may be tumor-promoting. Monocytosis in MF associated with rapid disease progression and short survival, suggesting an accelerated disease phase. Notably, monocytes share a common precursor with CD123+ pDCs. Tagraxofusp, a novel CD123 targeted therapy, demonstrated high activity in patients with BPDCN, an aggressive hematologic malignancy derived from CD123+ pDCs, and is FDA approved in BPDCN. As such, tagraxofusp may offer a novel therapeutic approach in MF. Methods: Multicenter, 2-stage Ph 1/2 trial enrolling patients (pts) with MF relapsed, refractory, or intolerant to JAKi. Objectives: determine optimal dose, evaluate safety and efficacy. Stage 1 dose escalation: IV tagraxofusp (7, 9, and 12 mcg/kg/day) dosed daily days 1-3 every 21 days (C1-4), 28 days (C5-7), and 42 days (C8+). Stage 2 (ongoing): pts receive optimal S1 dose (12 mcg/kg/day; no MTD). Results: 23 r/r pts treated. Median age 69 (55-81); 57% female. DIPSS Plus: 4% INT-1, 55% INT-2, 41% high. Baseline platelets: median 59 K/uL (15-579); 70% (16/23) <100 K/uL, 8 pts <50 K/uL. 87% (20/23) baseline splenomegaly (palpable ≥5 cm below left costal margin by physical exam). Most common TRAEs: headache (22%), hypoalbuminaemia (22%), ALT incr. (17%) and thrombocytopenia (17%). Most common ≥Gr3 TRAE thrombocytopenia (2%). Capillary leak syndrome in 1 pt (4%; Gr3). 57% (8/14) of pts with baseline spleen ≥5cm BCM spleen responses: 43% (6/14) had ≥29% and 21% (3/14) had ≥45% reduction. 100% of pts with baseline spleen ≥5cm and monocytosis splenomegaly reductions: 80% (4/5) had ≥29% and 40% (2/5) had ≥45%. 6 pts (3 monocytosis pts and 5 pts platelets <100 K/uL) had 6 mos+ duration, 9 pts ongoing. Conclusions: Tagraxofusp demonstrated single agent activity (reduction in splenomegaly) and manageable safety in R/R MF, including pts with monocytosis, an unmet medical need. Given the presence of CD123+ pDCs, tagraxofusp may offer a novel targeted approach in MF. Updated data to be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253.

Background Patients with myelofibrosis (MF) who fail or are intolerant to JAK inhibitors (JAKi) have limited treatment options. Tagraxofusp is a targeted therapy directed to CD123 that was approved by the FDA for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). CD123 is expressed on a variety of malignancies including BPDCN, acute myeloid leukemia (AML), and certain myeloproliferative neoplasms (MPN), including MF. High-expressing CD123+ plasmacytoid dendritic cells (pDCs), the cell of origin of BPDCN, have been detected in the microenvironment of certain myeloid neoplasms, including MF, where they may play a tumor-promoting role. Notably, pDCs share a common precursor cell with monocytes, and monocytosis has been reported as a poor prognostic factor in patients with MF, associated with shortened overall survival. We hypothesized that tagraxofusp may offer a novel and rational therapeutic approach in patients with relapsed/refractory MF, and in particular in patients with monocytosis. Aims To assess safety and evaluate efficacy of tagraxofusp in patients with MF who were relapsed, refractory, or unable to tolerate JAKi. Methods This multicenter, open-label Phase 1/2 trial is enrolling patients with MF. In the Stage 1 (dose escalation), tagraxofusp was administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days 1-3 every 21 days (cycle 1-4), 28 days (cycles 5-7), and 42 days (cycles 8+). In Stage 2 (expansion), patients are receiving the recommended Phase 2 dose (12 mcg/kg). Results 27 patients with MF have been treated, including 14 patients who had previously received ≥ 3 lines of therapy. Median age was 69 years (range 54-81), 52% were female, and 26% had baseline monocytosis (≥ 1x109/L). Baseline risk assessment based on the DIPSS Plus risk group assessment showed 1 patient (4%) with intermediate-1, 16 patients (59%) with intermediate-2, and 9 patients (33%) with high-risk. At study entry, median platelet count was 59 K/uL; 67% of patients had baseline platelets &lt;100 K/uL, of which 10 patients had platelets &lt;50 K/uL. 74% of patients had baseline splenomegaly (spleen palpable ≥ 5 cm below the left costal margin). In terms of molecular mutations: JAK2 (n=18); CALR (n=3); and MPL (n=1), and additional molecular analysis showed ASXL1 (n=5). In terms of cytogenetics, 30% (8/27) of patients had an abnormal karyotype, mainly 20q- (n=3), -5/5q-, -7/7q-, and 12p- (each n=2). Most common treatment-related adverse events (TRAEs, incidence ≥ 15%) include headache, hypoalbuminemia, increased levels of alanine aminotransferase, thrombocytopenia, and anemia. Most common ≥ grade 3 TRAE's were thrombocytopenia (8%) and anemia (15%). Capillary leak syndrome was reported in 1 patient (grade 3). Among the 17 evaluable patients with baseline splenomegaly, 53% had spleen size reductions, of which 4 patients had reductions of &gt; 45%. In 5 patients with baseline splenomegaly and monocytosis (&gt;1x109/L monocytes), 80% (4/5) had spleen size reductions, of which 2 had reductions of &gt;45%. Five patients had treatment duration of 12 months or more, with two of those patients ongoing (13+,and 24+ months, respectively). Six patients with platelets &lt;100 K/uL had treatment duration of 6 months or more, including 3 patients with baseline monocytosis who had treatment duration of 12 months or more. 7 patients had objective responses (IWG-MRT 2013 responses), including Clinical improvement (CI) (n=5) and CI (Symptom) (n=2). 20 patients were evaluable for symptomatic assessment (MPN-SAF TSS). Symptom response rate was 45% (defined as ³50% reduction in TSS score). Reductions in both symptom score and spleen size was noted in 6/6 patients who had splenomegaly at baseline. Conclusions Tagraxofusp demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF, including in patients with monocytosis, a poor prognostic factor and unmet medical need. Tagraxofusp may offer MF patients, and MF patients with monocytosis in particular, a novel treatment option. Enrollment continues, and updated trial data will be presented. This clinical trial is registered at clinicaltrials.gov: NCT02268253. Disclosures Pemmaraju: affymetrix: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; incyte: Consultancy, Research Funding. Gupta:Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding. Yacoub:Dynavax: Equity Ownership; Cara: Equity Ownership; Ardelyx: Equity Ownership; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Agios: Speakers Bureau; Hylapharm: Equity Ownership. Wang:Agios: Other: Advisory role; Amgen: Other: Advisory role; Daiichi: Other: Advisory role; Stemline: Other: Advisory role, Speakers Bureau; Pfizer: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau. Lee:AstraZeneca Pharmaceuticals: Consultancy; Ai Therapeutics: Research Funding; Karyopharm Therapeutics: Consultancy; Roche Molecular Systems: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Helsinn: Consultancy. Schiller:Agios: Research Funding, Speakers Bureau; Karyopharm: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Poradosu:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. McDonald:Stemline Therapeutics: Employment, Equity Ownership. Rupprecht:Stemline Therapeutics: Employment, Equity Ownership. Talpaz:Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Taparia:Novartis: Consultancy. Verstovsek:Protaganist Therapeutics: Research Funding; Ital Pharma: Research Funding; Astrazeneca: Research Funding; Pharma Essentia: Research Funding; Sierra Oncology: Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Khoury:Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.