Gupta, Vikas

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Abstract Idasanutlin, an MDM2 antagonist, showed clinical activity and a rapid reduction in JAK2 V617F allele burden in patients with polycythemia vera (PV) in a phase 1 study. This open-label phase 2 study evaluated idasanutlin in patients with hydroxyurea (HU)-resistant/-intolerant PV, per the European LeukemiaNet criteria, and phlebotomy dependence; prior ruxolitinib exposure was permitted. Idasanutlin was administered once daily on days 1 through 5 of each 28-day cycle. The primary end point was composite response (hematocrit control and spleen volume reduction > 35%) in patients with splenomegaly and hematocrit control in patients without splenomegaly at week 32. Key secondary end points included safety, complete hematologic response (CHR), patient-reported outcomes, and molecular responses. All patients (n = 27) received idasanutlin; 16 had response assessment (week 32). Among responders with baseline splenomegaly (n = 13), 9 (69%) attained any spleen volume reduction, and 1 achieved composite response. Nine patients (56%) achieved hematocrit control, and 8 patients (50%) achieved CHR. Overall, 43% of evaluable patients (6/14) showed a ≥50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (week 32). Nausea (93%), diarrhea (78%), and vomiting (41%) were the most common adverse events, with grade ≥ 3 nausea or vomiting experienced by 3 patients (11%) and 1 patient (4%), respectively. Reduced JAK2 V617F allele burden occurred early (after 3 cycles), with a median reduction of 76%, and was associated with achieving CHR and hematocrit control. Overall, the idasanutlin dosing regimen showed clinical activity and rapidly reduced JAK2 allele burden in patients with HU-resistant/- intolerant PV but was associated with low-grade gastrointestinal toxicity, leading to poor long-term tolerability. This trial was registered at www.clinincaltrials.gov as #NCT03287245.

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: The interleukin-3 receptor alpha chain (CD123) is a cell-surface target aberrantly expressed on various myeloid neoplasms including blastic plasmacytoid dendritic cell neoplasm (BPDCN), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). Tagraxofusp (TAG, SL-401), a first-in-class CD123-targeted therapy, is the only treatment approved by the FDA and EMA for patients (pts) with BPDCN. It has also been investigated in phase 1/2 clinical trials for AML (including pts with minimal residual disease [MRD]), CMML, and MF. We report the aggregated safety data of TAG monotherapy from trials in BPDCN, AML, CMML, and MF. Methods: An integrated safety analysis was performed for pts who received TAG monotherapy in three phase 1/2, multicenter clinical studies: Study 0114 (NCT02113982; BPDCN/AML), Study 0214 (NCT02270463; AML with/without MRD), and Study 0314 (NCT02268253; CMML/MF; Table 1). Pts received the recommended phase 2 dose of 12 mcg/kg/day (d) IV on d1-3 (MF and CMML) or d1-5 (BPDCN and AML) and were analyzed for incidence and timing of treatment-related adverse events (TRAEs), AEs of interest, and discontinuations. Safety data for TAG monotherapy, reported as individual case study reports (ICSRs) postapproval (US) and from an early access program (EAP; EU) are also presented. Results: In total, 201 pts receiving TAG (12 mcg/kg/d) in a clinical trial setting were included: BPDCN, n=86; AML, n=36; AML with/without MRD, n=10; CMML, n=33; MF, n=36. As of Jul 2021, 11 (6%) pts discontinued TAG due to any-grade (Gr) TRAE. Most common TRAEs (any-Gr) are shown in Table 2 and included hypoalbuminemia (41%), increased alanine aminotransferase (ALT; 40%), increased aspartate aminotransferase (AST; 39%), and thrombocytopenia (26%). The most common Gr ≥3 TRAEs were thrombocytopenia (n=41; 20%), increased AST (n=40; 20%), and increased ALT (n=35; 17%). Tumor lysis syndrome occurred in 5% of pts and 1.5% had infusion-related reactions. Any-Gr and Gr ≥3 hematologic TRAEs are presented in Table 3. Most common was thrombocytopenia. All TRAEs were transient in nature; prolonged bone marrow suppression was not observed. Overall, 23% (47/201) of pts experienced ≥1 treatment-related serious AE. Onset of most TRAEs, irrespective of Gr, commonly occurred in cycle 1 and resolved by cycle 2. Although the number of pts in cycles ≥2 was lower than in cycle 1, the incidence rates of common TRAEs also substantially decreased in subsequent cycles. Capillary leak syndrome (CLS) occurred in 17% of the overall 201 pts. The majority of all CLS events were nonsevere, Gr ≤2 (n=22; 63%); also reported were Gr 3, n=10 (29%); Gr 4, n=3 (9%), and 2 pts experienced a Gr 5 event. Onset of CLS was usually within the first week of cycle 1 (median time to onset [range], d: 5.5 [1-51]) and resolved quickly (median time to resolution [range], d: 5.0 [2-69]); no pts experienced the first onset after cycle 2. Of the 15 pts who resumed treatment after an initial CLS event, only 1 pt experienced a recurrence. The most common AEs reported as ICSRs postapproval and from an EAP (December 2018 to June 2021) were CLS, blood albumin decreased, thrombocytopenia, pyrexia, and hepatic enzyme increased. No new safety signals that would alter the safety profile were observed. Conclusions: This integrated analysis represents the largest collection of safety data (N=201) following treatment with TAG monotherapy. TAG has an established and manageable safety profile, with the vast majority of AEs reported as transient and decreasing in frequency/severity with increasing cycles. CLS was reported in 17% of pts; onset was usually within cycle 1, resolved quickly (median time to resolution: 5.0 d) by early intervention measures including holding treatment, and no pts experienced first onset after cycle 2. Risk-minimization guidelines for CLS were developed and implemented during clinical trials and incorporated into prescribing information. No myelosuppression or cumulative toxicity was observed over multiple treatment cycles. The safety profile observed postapproval and in the EAP was consistent with the clinical trial data reported, reflecting successful adoption of risk-management strategies in real-world practice. These data confirm the favorable benefit-risk profile of TAG monotherapy has been maintained in the 3 years following US approval. Figure 1 Figure 1. Disclosures Pemmaraju: ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Incyte: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Pacylex Pharmaceuticals: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Samus: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, 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; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; DAVA Oncology: Consultancy; Plexxicon: Other, Research Funding; Roche Diagnostics: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; ImmunoGen, Inc: Consultancy. Kantarjian: NOVA Research: Honoraria; Aptitude Health: Honoraria; Immunogen: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Jazz: Research Funding; Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; AbbVie: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria. Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; DAVA Oncology: Consultancy, Speakers Bureau; 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; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Takeda: 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; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; 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. Lane: N-of-One: Consultancy, Honoraria; Stemline Therapeutics: Research Funding; Qiagen: Consultancy, Honoraria; AbbVie: Research Funding. 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. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. 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. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; AROG: Other; Amgen: Other: personal fee; Bayer: Consultancy, Honoraria; Kite: Other: personal fee; Mustang: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Other: personal fee; Gilead: Other: personal fee; Jazz: Other: personal fee; Pharmacyclics: Other. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Gupta: AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Lee: BMS: 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; Innate: 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: Sangamo: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; FujiFilm: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Karyopharm: Research Funding; Onconova: Research Funding; Celator: Research Funding; Actuate: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Trovagene: Research Funding; Deciphera: Research Funding; Gamida Cell Ltd.: Research Funding; Forma: Research Funding; Ono-UK: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding; Takeda: Research Funding; Geron: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; PrECOG: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Mateon: Research Funding; Constellation Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Tolero: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Samus: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Ariad: 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; 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: trillium: Research Funding; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; OncLive: Honoraria; servier: Honoraria; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; abbvie: Research Funding; certara: Honoraria; bms: Honoraria; pfizer: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Walter: Macrogenics: Consultancy, Research Funding; Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Sieminski: Stemline Therapeutics: Current Employment, Current holder of stock options in a privately-held company. 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. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Konopleva: Calithera: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding.

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.