Search

Mutation-selective drugs constitute a great advancement in personalized anticancer treatment with increased quality of life and overall survival in cancers. However, the high adaptability and evasiveness of cancers can lead to disease progression and the development of drug resistance, which cause recurrence and metastasis. A common characteristic in advanced neoplastic cancers is the epithelial-mesenchymal transition (EMT) which is strongly interconnected with H2O2 signaling, increased motility and invasiveness. H2O2 relays its signal through the installation of oxidative posttranslational modifications on cysteines. The increased H2O2 levels that are associated with an EMT confer a heightened sensitivity towards the induction of ferroptosis as a recently discovered vulnerability.

Background Informal caregivers to intensive care unit (ICU) survivors may develop post-intensive care syndrome family (PICS-F), including depression, anxiety and post-traumatic stress (PTS). Our primary aim was to investigate associations between caregiver burden in informal caregivers cohabiting with ICU survivors and patients’ physical and psychological outcomes. Methods A prospective, multicentre cohort study in four ICUs in Sweden. Adults cohabiting with ICU patients included in a previous study were eligible for inclusion. Three months post-ICU, informal caregivers received questionnaires assessing caregiver burden, health-related quality of life (HRQL) and symptoms of depression, anxiety and PTS. In parallel, patients reported their three-month physical and psychological status via validated questionnaires. The primary outcome of this study was to compare caregiver burden in informal caregivers to patients with and without adverse physical and psychological outcomes 3 months post-ICU. Secondary outcomes were correlations between caregiver burden and informal caregivers’ mental HRQL. Results Among 62 included informal caregivers, 55 (89%) responded to the follow-up questionnaires. Caregiver burden was higher among informal caregivers to patients with an adverse outcome, compared to informal caregivers to patients without an adverse outcome, caregiver burden scale score mean (±standard deviation) 52 (11) and 41 (13) respectively (p = 0.003). There was strong negative correlation between caregiver burden and informal caregivers’ mental HRQL (rs −0.74, p

Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve overall survival (OS) in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). Use of these effective monoclonal antibodies in the frontline setting may lead to deep and durable remissions in older adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL. Methods: Patients (pts) ≥60 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was initially given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m2 and 2.7 mg/m2, respectively. Results: 73 pts have been treated, 70 of whom are evaluable for efficacy (3 pts too early for response assessment). 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics of the 70 evaluable pts are summarized in Table 1. Median age was 68 years (range, 60-81 years); 29 pts (41%) were ≥70 years. 41% were positive for TP53 mutation, 18% were CRLF2 positive by flow cytometry, and 27% had adverse-risk karyotype. 38/64 pts (59%) were CD20+ and received rituximab. Among 64 pts evaluable for morphologic response, 63 (98%) responded (CR, n=56; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 53/66 pts (80%) after 1 cycle and 65/68 pts (96%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 69 pts who achieved remission, 9 (13%) relapsed, 3 (4%) underwent allogeneic SCT in first remission (1 of whom subsequently relapsed), 35 (51%) remain on treatment or have completed therapy, and 21 (32%) died in CR/CRp. Notably, 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/70 (9%) with no difference in rate of VOD in pts who did or did not receive fractionated INO and blinatumomab. With a median follow-up of 45 months (range, 2-98 months), the 4-year continuous remission and OS rates were 78% and 50%, respectively (Figure 1A). Age and cytogenetic risk were the primary factors associated with OS. The 4-year OS rate was 61% in pts 60-69 years vs. 34% in pts ≥70 years (P=0.06), driven by higher rates of death in remission in the older pts (13/29 [45%] vs. 8/41 [20%] in pts 60-69 years of age; P=0.03). These remission deaths in pts ≥70 years were primarily due to infection (n=7) or development of MDS/AML (n=3). Pts with high-risk cytogenetic features (e.g. KMT2A rearranged, low hypodiploidy/near triploidy, complex cytogenetics) had a 4-year OS rate of 22% vs. 57% for patients without high-risk cytogenetic features (Figure 1B; P=0.009). Neither CRLF2 positivity by flow cytometry nor the presence of a TP53 mutation significantly impacted OS. Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 4-year OS rate of 50%. This novel regimen leads to durable remissions and apparent cure in the majority of pts age 60-69 years of age and in those without poor-risk cytogenetic features. To decrease treatment-related mortality, the protocol has been amended to eliminate chemotherapy for pts ≥70 years of age. Disclosures Short: Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy. Kantarjian:Janssen: Honoraria; Abbvie: Honoraria, Research Funding; Immunogen: Research Funding; Oxford Biomedical: Honoraria; Delta Fly: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BioAscend: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Astra Zeneca: Research Funding; Cyclacel: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Pulmotec: Research Funding. Alvarado:FibroGen: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; BerGenBio ASA: Research Funding; Jazz Pharmaceuticals: Research Funding. Burger:Janssen Pharmaceuticals: Consultancy, Speakers Bureau; TG Therapeutics: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding. Daver:Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Borthakur:Abbvie: Research Funding; Jannsen: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; AstraZeneca: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Consultancy; Argenx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; PTC Therapeutics: Research Funding; GSK: Research Funding; FTC Therapeutics: Consultancy; Cyclacel: Research Funding; BioLine Rx: Consultancy; BioLine Rx: Research Funding. DiNardo:Novartis: Consultancy; ImmuneOnc: Honoraria; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Jazz: Honoraria. Konopleva:Forty-Seven: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Amgen: Consultancy; Ablynx: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Sanofi: Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; F. Hoffmann La-Roche: Consultancy, Research Funding. Pemmaraju:Plexxikon: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Incyte Corporation: Honoraria; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Affymetrix: Other: Grant Support, Research Funding; SagerStrong Foundation: Other: Grant Support; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; DAVA Oncology: Honoraria; Novartis: Honoraria, Research Funding; Roche Diagnostics: Honoraria; MustangBio: Honoraria. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; H3 Biomedicine: Research Funding; Onconova: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Kite, Regeneron, Acerta: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin and blinatumomab - frontline treatment of ALL

7011 Background: INO and Blina improve overall survival (OS) in patients (pts) with relapsed/refractory B-ALL. The use of these agents in older adults in the frontline setting may allow for use of less chemotherapy and improve remission duration and OS compared to standard therapies. Methods: Pts ≥60 years with newly diagnosed Ph-negative B-cell ALL received mini-HCVD for up to 8 cycles. Initially, INO was given at 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. Beginning with pt #50, INO was given in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and 4 cycles of Blina were given following 4 cycles of mini-HCVD plus INO. Maintenance was with 12 cycles of POMP and 4 cycles of Blina (1 cycle of Blina after 3 cycles of POMP). Results: Characteristics of the 80 pts are shown in Table. 6 pts were in complete remission (CR) at enrollment. Among 74 evaluable pts, 73 (99%) responded (CR in 89%). MRD negativity by flow was achieved in 80% of pts after 1 cycle and in 94% overall. The 30-day mortality rate was 0%. Among 79 responders, 11 (14%) relapsed, 4 (5%) underwent SCT, 33 (42%) remain in ongoing continuous remission, and 31 (39%) died in remission. Notably, 6 pts (8%) developed veno-occlusive disease, 1 after subsequent SCT. With a median follow-up of 55 months, the 5-year continuous remission and OS rates were 76% and 47%, respectively. Age ≥70 and poor-risk cytogenetics were associated with worse outcomes. The inferior outcomes in pts ≥70 years was primarily due to higher rates of death in CR. The 5-year OS for pts age 60-69 years without poor-risk cytogenetics (n=37), age 60-69 with poor-risk cytogenetics (n=13), age ≥70 without poor-risk cytogenetics (n=24) and age ≥70 with poor-risk cytogenetics (n=6) were 69%, 39%, 36% and 0%, respectively. Conclusions: The combination of mini-HCVD plus INO, with or without Blina, in older adults with newly diagnosed Ph-negative ALL resulted in an overall response rate of 99% and a 5-year OS rate of 47%. Particularly favorable outcomes were seen in pts age 60-69 years without poor-risk cytogenetics (5-year OS: 69%). Chemotherapy-free regimens may improve outcomes in pts age ≥70 years, and novel agents/regimens are still needed for those with poor-risk cytogenetics. Clinical trial information: NCT01371630. [Table: see text]

BackgroundInformal caregivers to intensive care unit (ICU) survivors may develop post-intensive care syndrome family (PICS-F), including psychological problems such as depression, anxiety and post-traumatic stress (PTS). Our primary aim was to investigate associations between caregiver burden in informal caregivers cohabiting with ICU survivors and patients’ physical and psychological outcomes.MethodsWe conducted a prospective, multicentre cohort study in four ICUs in Sweden. Adults cohabiting with ICU patients included in a previous study were eligible for inclusion. Three months post-ICU, informal caregivers received questionnaires assessing perceived caregiver burden, health-related quality of life (HRQL) and symptoms of depression, anxiety and PTS. In parallel, patients reported their physical and psychological status via validated questionnaires. The primary outcome was to compare caregiver burden in informal caregivers to patients with and without adverse physical and psychological outcomes three months post-ICU. Secondary outcomes were correlations between caregiver burden and informal caregivers’ psychological status and mental HRQL.ResultsAmong 62 included informal caregivers, 55 (89%) responded to the follow-up questionnaires. Caregiver burden was higher in informal caregivers to patients with an adverse psychological or physical outcome, compared to informal caregivers to patients without an adverse outcome, caregiver burden scale score mean (±standard deviation) 52 (11) and 41 (13) respectively (p=0.003). There was strong negative correlation between caregiver burden and informal caregivers’ mental HRQL (rs -0.74, pConclusionInformal caregivers to ICU survivors with an adverse physical or psychological outcome experience a higher caregiver burden. A higher caregiver burden correlates with worse caregiver mental HRQL. ICU follow-up programs should consider screening and follow-up of informal caregivers for mental health problems.Trial registrationThe study was registered at clinicaltrials.gov, NCT02712541 on March 18 2016.

Background: Gilteritinib improves response rates and overall survival (OS) compared with chemotherapy in patients (pts) with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML). For older pts with newly diagnosed (ND) FLT3-mutated AML who are unfit for intensive chemotherapy, azacitidine plus venetoclax is the current standard of care, although remission durations are relatively short, largely due to FLT3-driven relapses. We therefore sought to evaluate the triplet regimen of azacitidine, venetoclax and gilteritinib for older pts with ND FLT3-mutated AML, as well as for those of all ages with R/R FLT3-mutated AML. Methods: In this phase I/II study, pts with either R/R FLT3-mutated AML or high-risk MDS/CMML or pts with ND FLT3-mutated AML who were unsuitable for intensive chemotherapy were eligible. FLT3-ITD and/or TKD mutations were allowed. Pts were required to have a performance status ≤3, total bilirubin ≤2.5 x ULN, ALT/AST ≤3 x ULN, and creatinine clearance ≥30 mL/min. In cycle 1, pts received azacitidine 75 mg/m 2 SC/IV on days 1-7, venetoclax on days 1-28, and gilteritinib on days 1-28. Gilteritinib dose ranged from 80mg to 120mg daily during the phase I dose escalation (3+3 design). Bone marrow was performed on day 14 and if blasts Results: Between 12/2019 and 7/2021, 26 pts were treated (11 ND pts and 15 R/R pts). Baseline characteristics are shown in Table 1. The median age for the ND and R/R cohorts were 71 years (range, 61-79) and 68 years (range, 19-90), respectively. In the ND cohort, 9 (82%) had a FLT3-ITD and 2 (18%) had a FLT3 TKD mutation; in the R/R cohort, 7 (47%) had a FLT3-ITD, 5 (33%) had a FLT3-TKD, and 3 (20%) had both mutations. Among pts in the R/R cohort, the median number of prior therapies was 2 (range, 1-5), 6 (40%) had poor risk cytogenetics, 5 (33%) had undergone prior hematopoietic stem cell transplant (HSCT), and 5 (33%) had received prior FLT3 inhibitor (including 1 pt who had received prior gilteritinib). Ten R/R pts were treated in the phase I cohort (6 at 80mg of gilteritinib and 4 at 120mg). No DLTs were observed at the 80mg daily dosing. Among 3 pts in the 120mg cohort who were evaluable for DLTs, 1 achieved MLFS but had prolonged grade 4 myelosuppression that met DLT criteria. Due to good clinical activity and superior count recovery observed with the 80mg dosing (with 3 of 6 pts [50%] in the phase I cohort achieving CR/CRp), the 80mg daily dose was chosen as the phase II dose for further study. In the entire R/R cohort, the median number of cycles received was 2 (range, 1-4). The overall response rate (CR+CRi+MLFS) was 67%. One pt (7%) achieved CR as best response, 3 (20%) achieved CRi, and 6 (40%) achieved MLFS. An additional pt with extramedullary-only disease achieved PR. Four pts (27% of the entire R/R cohort, 44% of responding pts) proceeded to HSCT. Among the 10 responding pts, 4 have relapsed (1 of whom was FLT3 negative), 2 died in morphologic remission, and 4 are still alive without relapse. The 30-day and 60-day mortality rates were 0% and 13%, respectively. With a median follow-up of 9.9 months in the R/R cohort, the median duration of response was 9.0 months and the median OS was 10.5 months (Figure 1A). In the ND cohort, the median number of cycles received was 2 (range, 1-6). All pts responded and all achieved marrow remission by day 14. Eight pts (73%) achieved CR as best response, 1 (9%) achieved CRi, and 2 (18%) achieved MLFS; the 3 pts with CRi/MLFS are still recovering from cycle 1 at the time of this report. Two pts (18%) proceeded to HSCT. With a median follow-up of 3.8 months (range, 0.5-8.7 months), no pts have relapsed and 1 pt died (Figure 1B). This pt achieved MRD-negative CR and died 9 weeks into therapy due to sepsis. Conclusions: The combination of azacitidine, venetoclax and gilteritinib was effective in pts with FLT3-mutated AML. Gilteritinib dosing at 80mg daily was associated with a better safety/efficacy profile and was selected for future study; however, even with this lower dose myelosuppression was common and required attenuation of azacitidine and venetoclax. This combination appears particularly encouraging in the frontline setting where the response rate was 100% with no relapses observed to date. Figure 1 Figure 1. Disclosures Short: Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. DiNardo: Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria. Daver: Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novimmune: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kadia: Genfleet: Other; Astellas: Other; AstraZeneca: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Liberum: Consultancy; BMS: Other: Grant/research support; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Ascentage: Other; Novartis: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Dalichi Sankyo: Consultancy; Amgen: Other: Grant/research support. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Borthakur: Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Konopleva: F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; KisoJi: Research Funding; Sanofi: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support. Kantarjian: Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Agios: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Gilteritinib for frontline treatment of FLT3-mutated AML

Background: Inotuzumab ozogamicin (INO) and blinatumomab are effective in the treatment relapsed/ refractory B-cell acute lymphoblastic leukemia (ALL) and improve overall survival (OS) in this setting. The use of these agents in older adults with newly diagnosed B-cell ALL may allow for use of less chemotherapy and improve remission durations and OS compared to standard therapies. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m 2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m 2 on day 3 of cycle 1 and 0.8-1.3mg/m 2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m 2 on day 2 and 0.3 mg/m 2 on day 8 of cycle 1; 0.3 mg/m 2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m 2 and 2.7 mg/m 2, respectively. Results: 75 pts have been treated. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphological response. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-87 years); 30 pts (40%) were ≥70 years. 39% were positive for TP53 mutation, 19% had Ph-like ALL (with 6 of the 8 Ph-like pts being CRLF2+ by flow), and 25% had adverse-risk karyotype. Among 69 pts evaluable for morphologic response, 68 (99%) responded (CR, n=61; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 57/71 pts (80%) after 1 cycle and 71/74 pts (96%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 74 pts who achieved remission, 10 (14%) relapsed, 4 (5%) underwent allogeneic SCT in first remission (1 of whom subsequently relapsed), 32 (43%) remain on treatment or have completed therapy, and 28 (38%) died in remission. Overall, 9 pts (12%) developed MDS/AML; in 7 of these cases the myeloid malignancy was TP53-mutated and in the 2 other cases, both the ALL and subsequent AML shared mutations in myeloid mutations (RUNX1, SRSF2, and TET2). Notably, 6 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/75 (8%) with no difference in VOD in pts who did or did not receive blinatumomab. With a median follow-up of 56 months (range, 1-111 months), the 5-year continuous remission and OS rates were 76% and 47%, respectively (Figure 1A). Outcomes were superior for those 60-69 years of age versus those who were ≥70 years (5-year OS rates: 58% and 31%, respectively; P=0.04) and for those without poor-risk cytogenetics (e.g. KMT2A rearranged, low hypodiploidy/near triploidy, complex cytogenetics) versus poor-risk cytogenetics (5-year OS rates: 56% and 25%, respectively; P=0.01). Pts ≥70 years of age were more likely to die in remission (20/29 [69%] vs. 19/45 [42%] in pts 60-69 years of age; P=0.03), which was a major driver of the poor survival in this age group. The 5-year OS for pts age 60-69 years with non-poor risk cytogenetics, age 60-69 with poor risk cytogenetics, age ≥70 with non-poor risk cytogenetics and age ≥70 with poor risk cytogenetics were 68%, 37%, 42% and 0% respectively (Figure 1B). Neither Ph-like ALL nor the presence of a TP53 mutation significantly impacted OS (P=0.26 and P=0.34, respectively). Conclusion: Low-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, in older adults with newly diagnosed Ph-negative ALL resulted in an overall response rate of 98% and a 5-year OS rate of 47%. Even with this relatively reduced-intensity regimen, deaths in remission (usually due to infection) occur, primarily in pts ≥70 years of age. A strategy using the combination INO and blinatumomab, without any chemotherapy, is being explored in this population. Figure 1 Figure 1. Disclosures Short: NGMBio: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: BMS: Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Jazz: Research Funding; Daiichi-Sankyo: Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Novartis: Honoraria; AbbVie: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Amgen: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria. Jain: Janssen: Honoraria; TG Therapeutics: Honoraria; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kadia: Genfleet: Other; AstraZeneca: Other; Genentech: Consultancy, Other: Grant/research support; Jazz: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Cure: Speakers Bureau; Aglos: Consultancy; Sanofi-Aventis: Consultancy; Pulmotech: Other; Dalichi Sankyo: Consultancy; BMS: Other: Grant/research support; Cellonkos: Other; Pfizer: Consultancy, Other; Astellas: Other; Ascentage: Other; Novartis: Consultancy; Liberum: Consultancy; Amgen: Other: Grant/research support. Khoury: Kiromic: Research Funding; Stemline Therapeutics: Research Funding; Angle: Research Funding. Wang: Stemline Therapeutics: Honoraria. Alvarado: Astex Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Sun Pharma: Consultancy, Research Funding. Burger: Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Trovagene: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo: Bristol Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Konopleva: AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; KisoJi: 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; AstraZeneca: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Ascentage: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding. Pemmaraju: Daiichi Sankyo, Inc.: Other, Research Funding; Springer Science + Business Media: Other; LFB Biotechnologies: Consultancy; Celgene Corporation: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; MustangBio: Consultancy, Other; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; DAVA Oncology: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Affymetrix: Consultancy, Research Funding; 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; Clearview Healthcare Partners: Consultancy; Roche Diagnostics: Consultancy; Sager Strong Foundation: Other; Aptitude Health: Consultancy; CareDx, Inc.: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Wierda: Miragen: Research Funding; GSK/Novartis: Research Funding; Loxo Oncology, Inc.: Research Funding; Acerta Pharma Inc.: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Xencor: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. O'Brien: Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. OffLabel Disclosure: Blinatumomab and inotuzumab as frontline therapy for B-cell ALL

Background: Blinatumomab is highly effective therapy for both the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and persistent or recurrent measurable residual disease (MRD) after initial ALL therapy. We hypothesized that early incorporation of blinatumomab in patients (pts) with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell ALL would lead to deeper and more durable responses, reduce relapses, and improve survival. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl, creatinine ≤2 mg/dl, and no significant CNS pathology (with the exception of CNS leukemia). Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m 2). Eight administrations of prophylactic IT chemotherapy were given in the first 4 cycles. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). Beginning with pt #10, those with high-risk disease features (e.g. CRLF2+ by flow cytometry, complex karyotype, KMT2A rearranged, low-hypodiploidy/near triploidy, TP53 mutation, or persistent MRD) started blinatumomab after 2 cycles of hyper-CVAD. Results: 38 evaluable pts have been treated. 6 pts were in complete remission (CR) at enrollment and unevaluable for morphologic response. Pt characteristics of the 38 evaluable pts are summarized in Table 1. Median age was 37 years (range, 17-59 years). At least one high-risk feature was present in 21 pts (55%), including TP53 mutation in 27%, CRLF2+ in 19%, and an adverse-risk karyotype in 32%. 84% of pts received ofatumumab or rituximab. Among 32 pts with active disease at study entry, 100% achieved CR, with 81% achieving CR after the first cycle (Table 1). MRD negativity by 6-color flow cytometry was achieved in 22/26 responding pts (85%) after 1 cycle and 37/38 pts (97%) overall. The 60-day mortality rate was 0%. With a median follow-up of 27 months (range, 11-55 months), the 3-year continuous remission and OS rates were 80% and 83%, respectively (Figure 1). Overall, 5 pts (13%) relapsed, 13 (34%) underwent allogeneic SCT in first remission (including 2 additional pts who relapsed post-SCT), 1 died in CR (possible pulmonary embolism), and 19 (50%) remain in continuous remission and are currently on treatment or have completed maintenance. All relapses occurred in pts with established poor-risk features and no relapses have occurred beyond 2 years from the start of treatment. OS with hyper-CVAD plus blinatumomab compares favorably to a historical cohort of pts treated with hyper-CVAD plus ofatumumab (3-year OS 83% versus 66%, respectively; P=0.2). Treatment was overall well-tolerated. Four pts developed grade 2-3 cytokine release syndrome (grade 2, n=3; grade 3, n=1) which resolved with corticosteroids and interruption of blinatumomab. Overall, 16 (42%) pts had a neurological adverse event of any grade due to blinatumomab. Four pts (11%) developed grade 3 neurologic toxicity related to blinatumomab, all of which was transient and reversible. Only one pt discontinued blinatumomab due to blinatumomab-related adverse event (grade 2 encephalopathy and dysphasia). Conclusion: Hyper-CVAD with sequential blinatumomab is highly effective as frontline treatment of Ph-negative B-cell ALL, with an overall MRD negativity rate of 97% and a 3-year OS rate of 83%. This study shows the potential benefit of incorporating frontline blinatumomab into the treatment of younger adults with ALL and also shows that reduction of chemotherapy in this context is feasible. Figure 1 Figure 1. Disclosures Short: Novartis: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: Precision Biosciences: Honoraria; Immunogen: Research Funding; Jazz: Research Funding; Astra Zeneca: Honoraria; KAHR Medical Ltd: Honoraria; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Astellas Health: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Taiho Pharmaceutical Canada: Honoraria. Ravandi: Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; AstraZeneca: Honoraria; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding. Thompson: Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Gilead: Other: Institution: Advisory/Consultancy, Honoraria; AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Janssen: Consultancy, Honoraria; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; AstraZeneca: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board . Kadia: Astellas: Other; Genentech: Consultancy, Other: Grant/research support; Sanofi-Aventis: Consultancy; Cellonkos: Other; Pfizer: Consultancy, Other; Pulmotech: Other; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Novartis: Consultancy; BMS: Other: Grant/research support; AstraZeneca: Other; Liberum: Consultancy; Ascentage: Other; Genfleet: Other; Jazz: Consultancy; Dalichi Sankyo: Consultancy; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Jain: Janssen: Honoraria; Precision Biosciences: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Incyte: Research Funding; Servier: Honoraria, Research Funding; Beigene: Honoraria; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria; Pfizer: Research Funding; Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Alvarado: Sun Pharma: Consultancy, Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; CytomX Therapeutics: Consultancy; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; MEI Pharma: Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Wang: Stemline Therapeutics: Honoraria. Konopleva: KisoJi: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Forty Seven: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. OffLabel Disclosure: Blinatumomab in the frontline setting for B-cell ALL

Background: Ponatinib and blinatumomab are both highly effective in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination of these two agents may lead to deep and durable responses, thereby reducing the need for both chemotherapy and allogeneic stem cell transplant (ASCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Patients (pts) were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and alanine aminotransferase and aspartate aminotransferase ≤3x the ULN. Pts with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Pts received up to 5 cycles of blinatumomab as a continuous infusion at standard doses. Ponatinib 30mg daily was given during cycle 1. Ponatinib was decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years in responding pts. Twelve doses of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate were administered. For pts with ND Ph+ ALL, the primary endpoint was the CMR rate. For pts with R/R Ph+ ALL, the primary endpoint was the overall response rate (defined as the composite of CR/CRi). Results: Between February 2018 and July 2021, 43 were treated (24 ND, 14 R/R and 5 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the ND and R/R Ph+ ALL cohorts were 60 years (range, 34-83) and 38 years (range, 24-61), respectively. BCR-ABL1 transcripts were p190 in 67% of pts in the ND cohort and 93% in the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in salvage 2 or beyond. Among 32 pts evaluable for morphologic response, all but 1 pt (97%) responded. Notably, the one non-responding pt had R/R Ph+ ALL and had previously received ponatinib in an earlier salvage regimen. The CR/CRi rate was 100% for ND pts, 91% for R/R pts, and 100% CML-LBP pts. 84% of responding pts achieved CMR (91% in the ND cohort, 91% in the R/R cohort, and 40% in the CML-LBP cohort). The CMR rates after 1 cycle were 64%, 82% and 20% in these 3 groups, respectively. Among 10 pts in the ND cohort who had peripheral blood PCR for BCR-ABL1 evaluated on day 7 of cycle 1, 3 (30%) had already achieved CMR at this early timepoint; 5 out of 13 evaluable patients (38%) had achieved CMR by days 14-21 of cycle 1 The median follow-up is 9 months (range, 1-38+ months). Among the 24 pts in the ND cohort, 1 pt died in CR, and the rest are all in ongoing response without HSCT in first remission, with a median CR duration of 8 months (range, 1-36+ months). The estimated 2-year EFS and OS for the ND cohort is 95% (Figure 1). Among the 14 pts in the R/R cohort, 2 are too early for response evaluation, 1 did not respond, 4 underwent ASCT (3 of whom are still alive without relapse and 1 of whom relapsed post-ASCT and died), 2 did not undergo ASCT and subsequently relapsed, 1 died in CR, and 4 are in ongoing response without ASCT. The estimated 2-year EFS and OS for the R/R cohort are 53% and 39%, respectively (Figure 1). Among the 5 pts in the CML-LBP cohort, 2 relapsed (1 of whom converted to myeloid immunophenotype) and 3 are in ongoing response without ASCT. The combination treatment was well-tolerated, and most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). No pts discontinued blinatumomab due to toxicity. No early deaths were observed. Conclusion: The chemotherapy-free combination of ponatinib and blinatumomab is a safe and effective regimen in both ND and R/R Ph+ ALL, as well as in CML-LBP. Given the particularly favorable outcomes of pts with ND Ph+ ALL who were not transplanted in first remission, these data suggest that this regimen may serve as an effective transplant-sparing regimen in this population. Figure 1 Figure 1. Disclosures Short: Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; NGMBio: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Kantarjian: Ascentage: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Aptitude Health: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Konopleva: Ascentage: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Cellectis: Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding. Jain: Aprea Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Janssen: Honoraria; ADC Therapeutics: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; AbbVie: Honoraria, Research Funding. Ravandi: Prelude: Research Funding; Agios: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; AstraZeneca: Honoraria; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Borthakur: University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sasaki: Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Alvarado: Daiichi-Sankyo: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; Cellectis S.A. ADR: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Springer Science + Business Media: Other; Aptitude Health: Consultancy; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Samus: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; LFB Biotechnologies: Consultancy; Dan's House of Hope: 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; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. DiNardo: Takeda: Honoraria; Novartis: Honoraria; ImmuneOnc: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Agios/Servier: Consultancy, Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. OffLabel Disclosure: Blinatumomab and ponatinib as frontline therapy for Ph+ ALL

Contains fulltext : 220789.pdf (Publisher’s version ) (Open Access) BACKGROUND: Methods to identify patients at risk for incomplete physical recovery after intensive care unit (ICU) stay are lacking. Our aim was to develop a method for prediction of new-onset physical disability at ICU discharge. METHODS: Multinational prospective cohort study in 10 general ICUs in Sweden, Denmark, and the Netherlands. Adult patients with an ICU stay ≥12 hours were eligible for inclusion. Sixteen candidate predictors were analyzed with logistic regression for associations with the primary outcome; new-onset physical disability 3 months post-ICU, defined as a ≥10 score reduction in the Barthel Index (BI) compared to baseline. RESULTS: Of the 572 included patients, follow-up data are available on 78% of patients alive at follow-up. The incidence of new-onset physical disability was 19%. Univariable and multivariable modeling rendered one sole predictor for the outcome: physical status at ICU discharge, assessed with the five first items of the Chelsea critical care physical assessment tool (CPAx) (odds ratio 0.87, 95% confidence interval (CI) 0.81-0.93), a higher score indicating a lower risk, with an area under the receiver operating characteristics curve of 0.68 (95% CI 0.61-0.76). Negative predictive value for a low-risk group (CPAx score >18) was 0.88, and positive predictive value for a high-risk group (CPAx score ≤18) was 0.32. CONCLUSION: The ICU discharge assessment described in this study had a moderate AUC but may be useful to rule out patients unlikely to need physical interventions post-ICU. For high-risk patients, research to determine post-ICU risk factors for an incomplete rehabilitation is mandated.

Purpose To develop an instrument for use at ICU discharge for prediction of psychological problems in ICU survivors. Methods Multinational, prospective cohort study in ten general ICUs in secondary and tertiary care hospitals in Sweden, Denmark and the Netherlands. Adult patients with an ICU stay ≥ 12 h were eligible for inclusion. Patients in need of neurointensive care, with documented cognitive impairment, unable to communicate in the local language, without a home address or with more than one limitation of therapy were excluded. Primary outcome was psychological morbidity 3 months after ICU discharge, defined as Hospital Anxiety and Depression Scale (HADS) subscale score ≥ 11 or Post-traumatic Stress Symptoms Checklist-14 (PTSS-14) part B score > 45. Results A total of 572 patients were included and 78% of patients alive at follow-up responded to questionnaires. Twenty percent were classified as having psychological problems post-ICU. Of 18 potential risk factors, four were included in the final prediction model after multivariable logistic regression analysis: symptoms of depression [odds ratio (OR) 1.29, 95% confidence interval (CI) 1.10–1.50], traumatic memories (OR 1.44, 95% CI 1.13–1.82), lack of social support (OR 3.28, 95% CI 1.47–7.32) and age (age-dependent OR, peak risk at age 49–65 years). The area under the receiver operating characteristics curve (AUC) for the instrument was 0.76 (95% CI 0.70–0.81). Conclusions We developed an instrument to predict individual patients’ risk for psychological problems 3 months post-ICU, http://www.imm.ki.se/biostatistics/calculators/psychmorb/. The instrument can be used for triage of patients for psychological ICU follow-up. Trial registration The study was registered at clinicaltrials.gov, NCT02679157. Electronic supplementary material The online version of this article (10.1007/s00134-018-5467-3) contains supplementary material, which is available to authorized users.