Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0·01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0·0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.

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Background: Gilteritinib, an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, demonstrated antileukemic responses in patients with FLT3-mutated (FLT3mut+) relapsed/refractory acute myeloid leukemia (AML). We report final results from a phase 1 study of once-daily oral gilteritinib plus intravenous (IV) chemotherapy in patients with newly diagnosed AML. Methods: This 4-part, open-label, phase 1 study (NCT02236013) assessed the safety/tolerability and antileukemic effects of gilteritinib plus 7+3 induction and high-dose cytarabine consolidation chemotherapy, and as single-agent maintenance therapy in adults with newly diagnosed AML. In part 1, successive cohorts of 3-6 patients received 40-200 mg/d gilteritinib (Days 4-17) and ≤2 cycles of induction (cytarabine 100 mg/m2/d IV, Days 1-7; idarubicin 12 mg/m2/d IV, Days 1-3). In part 2, patients (n=33, of which at least 15 were FLT3mut+) received the recommended 120 mg/d gilteritinib expansion dose and ≤2 cycles of the part 1 induction schedule. In part 3, patients were stratified into 2 cohorts: one receiving treatment from part 2 (n=7) and the other receiving treatment that replaced idarubicin with daunorubicin (90 mg/m2/d IV, Days 1-3; n=7). In part 4, patients (n=12) received the same induction as the part 3/daunorubicin cohort (with a reduction in cycle 2 to daunorubicin 45 mg/m2/d). During consolidation, patients received ≤3 cycles of cytarabine (1.5 g/m2 every 12 hours; Days 1, 3, and 5) and gilteritinib (Days 1-14 for parts 1-3; Days 1-56 for part 4) at the induction dose. Gilteritinib was given once daily in 28-day cycles for up to 26 cycles as maintenance therapy (maintenance phase is still ongoing). Patients achieving composite complete remission (CRc) or partial remission could undergo hematopoietic stem cell transplant (HSCT) and resume maintenance gilteritinib treatment post-HSCT. Results: As of 23 June 2020, 80 patients were allocated to treatment (safety analysis set, n=79); median age was 59.0 y (range, 23-77) and most were male (62.0%). Median follow-up for overall survival (OS) was 35.8 mo. Dose-limiting toxicities are provided in Table 1. The maximum tolerated dose was 120 mg/d. Serious treatment-related adverse events (AEs) and AEs leading to discontinuation of gilteritinib occurred in 12.7% (n=10) and 5.1% (n=4) of patients, respectively. One (1.3%) death occurred across all treatment phases. Grade ≥3 nonhematologic AEs (≥10% of patients) were increased alanine aminotransferase (13.9%), pneumonia (13.9%), sepsis (11.4%), and bacteremia (11.4%). At the end-of-induction time point, there were 44 (55.7%) total FLT3mut+ patients across all dose groups and 38 (48.1%) patients who received gilteritinib 120 mg/d. Investigator-reported CRc was achieved by 81.8% of patients across all dose groups (n=36) and 81.6% among patients who received gilteritinib 120 mg/d (n=31; Table 2). Anthracycline choice had no clear impact on CRc rate, although the number of patients in these cohorts was low. In FLT3mut+ patients who achieved CRc in any dose group, median (95% CI) duration of CRc and disease-free survival were 14.1 (4.0-29.9) and 15.3 (9.8-not reached) mo, respectively. Median OS for FLT3mut+ patients has not been reached. The survival probability (95% CI) in all FLT3mut+ patients at weeks 8, 12, 26, 52, and 104 were 97.7% (84.6%-99.7%), 95.3% (82.5%-98.8%), 92.9% (79.6%-97.7%), 83.1% (67.7%-91.5%), and 71.8% (54.6%-83.4%), respectively. In patients with FLT3 internal tandem duplication (ITD)-positive AML achieving CRc, mutational clearance (summed FLT3 ITD signal ratio of ≤10-4 after induction or consolidation) was achieved by 70% (n/N=16/23) of patients receiving a gilteritinib dose of ≥120 mg. HSCT occurred in 30.4% of the total population (n/N=24/79). Analysis of plasma inhibitory activity and pharmacokinetics of gilteritinib will be available at presentation. Conclusions: Gilteritinib plus induction and consolidation chemotherapy is well tolerated in patients with newly diagnosed AML. Favorable antileukemic responses were observed in FLT3mut+ patients regardless of anthracycline type or gilteritinib administration schedule, with a mutational clearance rate of 70.0%. Based on these results, randomized clinical trials of induction and consolidation chemotherapy plus gilteritinib vs midostaurin in FLT3mut+ AML patients have been initiated. Disclosures Pratz: AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Celgene: Other: Scientific Advisory Board; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding. Cherry:Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Kite: Other: Advisory Board. Altman:PeerView: Consultancy; ASH: Consultancy; Syros: Consultancy; Janssen: Consultancy; Genentech: Research Funding; Amphivena: Research Funding; Amgen: Research Funding; Aprea: Research Funding; ImmunoGen: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; PrIME Oncology: Consultancy; Immune Pharmaceuticals: Consultancy; Novartis: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Kartos: Research Funding; AbbVie: Other: advisory board, Research Funding; Fujifilm: Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Bristol-Myers Squibb: Consultancy; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Cancer Expert Now: Consultancy; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; France Foundation: Consultancy. Cruz:Takeda: Speakers Bureau. Jurcic:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Lin:Pfizer: Research Funding; Bio-Path Holdings: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Ono Pharmaceutical: Research Funding; Prescient Therapeutics: Research Funding; Incyte: Research Funding; Genetech-Roche: Research Funding; Gilead Sciences: Research Funding; Aptevo: Research Funding; Celyad: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Trovagene: Research Funding. Perl:Bayer HealthCare Pharmaceuticals: Research Funding; Syndax: Consultancy, Honoraria; Jazz: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Biomed Valley Discoveries: Research Funding; Agios: Consultancy, Honoraria, Other; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Takeda: Honoraria, Other: Travel costs for meeting; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; New Link Genetics: Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FORMA Therapeutics: Consultancy, Honoraria, Other; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Other, Research Funding. Podoltsev:Arog Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Sunesis Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Research Funding; Astellas Pharma: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Samus Therapeutics: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Kartos Therapeutics: Research Funding; AI Therapeutics: Research Funding. Schiller:Abbvie: Research Funding; Actinium: Research Funding; Ariad: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Kite Pharma: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company. Hill:Targeted Molecular Diagnostics: Patents & Royalties: US7862995; Astellas: Current Employment; Ligacept, LLC: Current equity holder in publicly-traded company, Patents & Royalties: US9051388, US9683222. James:Astellas: Current Employment. Lu:Astellas: Current Employment. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. OffLabel Disclosure: New Indication

Introduction: Gilteritinib is a novel, potent, highly-selective oral fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor. Once-daily single-agent gilteritinib doses of ≥80 mg/day elicited antileukemic responses in FLT3 mutation-positive (FLT3mut+) subjects with relapsed/refractory AML (Perl AE, et al. Lancet Oncol. 2017). We examined the safety/tolerability and antitumor activity of gilteritinib plus front-line intensive chemotherapy in newly diagnosed AML patients. Methods: This ongoing open-label, dose-escalation/expansion phase 1 study (NCT02236013) assesses the safety/tolerability and antitumor effects of gilteritinib combined with 7+3 induction and high-dose cytarabine consolidation, and as single-agent maintenance therapy in subjects aged ≥18 years with newly diagnosed AML (excluding core-binding factor translocations). Dose escalation followed a 3+3 design; successive cohorts of 3-6 subjects received 40, 80, 120, or 200 mg/day gilteritinib. Subjects received ≤2 cycles of a 7+3 induction regimen (cytarabine 100 mg/m2/day, Days 1-7 plus idarubicin 12 mg/m2/day, Days 1-3 [dose-escalation and dose-expansion cohorts], and once-daily gilteritinib on Days 4-17 [Schedule 1]). After completion of the dose-expansion cohort using Schedule 1, a new cohort of patients were enrolled. In this cohort of six patients, gilteritinib administration was changed to Days 8-21 (Schedule 2) in preparation for phase 3 studies and daunorubicin 90 mg/m2/day, administered on Days 1-3, was used as an alternative anthracycline to idarubicin. During consolidation, subjects received cytarabine (1.5 g/m2 every 12 hours, Days 1, 3, and 5) and once-daily gilteritinib (Days 1-14) at the induction dose for ≤3 cycles. Subjects in the dose-expansion cohort received gilteritinib at the recommended expansion dose established during dose escalation. Transplantation was allowed for responding subjects. After consolidation or transplantation with stable engraftment, subjects received maintenance therapy with once-daily gilteritinib (28-day cycles; ≤26 cycles). Results: As of July 2, 2018, 62 subjects have been enrolled; 60 are included in the safety analysis set. Most subjects were male (66.7%; median age, 59.5 years [range, 23-77]) and 32 (53.3%) had FLT3 mutations (FLT3-ITD, n=23). During dose-escalation, two subjects in the 40 mg/day cohort who had received gilteritinib on Days 1-14 experienced dose-limiting toxicities (DLTs; neutropenia, thrombocytopenia, decreased ejection fraction). After the gilteritinib induction schedule change, no more DLTs occurred at this dose. Two subjects in the 200 mg/day cohort experienced DLTs (neutropenia, neutropenic enterocolitis). The maximum tolerated dose and the recommended expansion dose were established at 120 mg/day. Grade ≥3 adverse events (AEs) in ≥10% of patients were febrile neutropenia (63.3%), thrombocytopenia (18.3%), decreased platelet count (16.7%), neutropenia (15.0%), bacteremia (10.0%), sepsis (10.0%), and decreased white blood cell count (10.0%). Serious drug-related AEs in >1 subject were febrile neutropenia (n=9), small intestinal obstruction, lung infection, sepsis, and decreased ejection fraction (all n=2). The end-of-treatment investigator-reported rate of composite complete remission (CRc) for response evaluable FLT3mut+ subjects receiving gilteritinib 120 mg on Schedule 1 (n=17) was 100%. The CRc rate in FLT3mut+ subjects receiving Schedule 2 induction with daunorubicin was also 100% (Table). Enrollment in the Schedule 2 cohort receiving idarubicin is ongoing; the two subjects in this cohort have not been assessed for response. Among subjects who received ≥80 mg/day gilteritinib (n=47), CRc rates for FLT3mut+ subjects were 88.9% (n=24/27). Median overall survival has not been reached. Median disease-free survival was 297 days (95% CI: 112, not reached). Assessment of minimum residual disease in FLT3-ITD patients using a next-generation sequencing-based assay is ongoing; results will be available at the time of presentation. Conclusions: Gilteritinib can be safely combined with intensive chemotherapy, and given as single-agent maintenance therapy in subjects with newly diagnosed AML. Treatment was well tolerated. High response rates were observed in FLT3mut+ subjects after treatment with either idarubicin or daunorubicin in combination with two different gilteritinib administration schedules. Disclosures Pratz: Millenium/Takeda: Research Funding; AbbVie: Consultancy, Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Altman:Astellas Pharma: Other; Agios: Other: Payment to the institution to conduct the trial ; Epizyme: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; GSK: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Cruz:Takeda: Speakers Bureau. Jurcic:Kura Oncology: Research Funding; Forma Therapeutics: Research Funding; Celgene: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy; Actinium Pharmaceuticals, Inc: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Syros Pharmaceuticals: Research Funding; Genetech: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Research Funding. Lin:Jazz Pharmaceuticals: Honoraria. Perl:AbbVie: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy; NewLink Genetics: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy. Podoltsev:Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Research Funding; LAM Therapeutics: Research Funding; Astex Pharmaceuticals: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Sunesis Pharmaceuticals: Research Funding; Daiichi Snakyo: Research Funding; Celator: Research Funding; Celgene: Research Funding; Pfizer: Research Funding. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Astellas Pharma: Employment. Bahceci:Astellas Pharma: Employment.