No abstract

Co-senior authors Andrew Brunner and Andrew H. Wei contributed equally to this work Background: MBG453 is a high-affinity humanized anti-TIM-3 (T-cell immunoglobulin domain and mucin domain-3) IgG4 antibody in development for the treatment of MDS, AML, and other malignancies. TIM-3 is an immune checkpoint with a complex regulatory role in both adaptive and innate immune responses and is also preferentially expressed on leukemic stem and progenitor cells, making it a potential target in MDS and AML. MBG453 has been shown to enhance immune cell-mediated killing of AML cells in vitro. Hypomethylating agents (HMAs) have been shown to increase immune checkpoint expression in MDS and AML, providing rationale to study the combination of HMAs with MBG453. Methods: Patients with Revised International Prognostic Scoring System (IPSS-R) high or very high-risk (HR) MDS and newly diagnosed, or relapsed/refractory (R/R), AML following ≥ 1 prior therapy who were not candidates for standard chemotherapy and who were HMA naive were enrolled in this multi-center, open label phase Ib dose-escalation study (NCT03066648). Escalating doses of MBG453 were administered i.v. every 2 weeks (Q2W; days 8, 22) or every four weeks (Q4W; day 8) in combination with decitabine (20 mg/m2; i.v. days 1-5). The primary objectives were to characterize the safety and tolerability of MBG453 in combination with decitabine and to identify recommended doses for future studies. Secondary objectives included assessing preliminary efficacy and pharmacokinetics of the combination. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs). Adverse events (AEs) were graded using NCI-CTCAE v4.03. The International Working Group criteria for MDS (Cheson et al, 2006) or AML (Cheson et al, 2003) were used to assess efficacy. Results: As of March 25, 2019, 17 HR-MDS, 4 chronic myelomonocytic leukemia (CMML), and 38 AML patients have received decitabine and MBG453 at 240 mg Q2W (n=22), 400 mg Q2W (n=21), or 800 mg Q4W (n=16). MTD has not been reached. Median age was 70 years (range 23-87 years). 24 patients are ongoing (duration of exposure 1.1 to 18.6 months) with 35 patients discontinued (disease progression [n=19, 32%], AE [n=1, 2%], patient/physician decision [n=13, 22%], death [n=2, 3%]). There was one DLT consisting of a grade 3 ALT elevation that was corticosteroid responsive. The most common treatment emergent grade 3/4 AEs were febrile neutropenia (39%), neutropenia (34%), thrombocytopenia (31%), and anemia (29%). A total of 8 patients (14%) developed ≥ grade 2 suspected immune related AEs (irAEs) considered to be MBG453 related; 4 of whom (7%) presented with grade 3/4 events: ALT elevation (n=2), arthritis (n=1), and GGT increase (n=1). No study treatment-related deaths were observed. 16 HR-MDS and 31 AML patients have had post-baseline disease response assessments. Median duration of decitabine and MBG453 is 3.9 months (range 0.7-18.6 months). Evidence of activity with MBG453 in combination with decitabine has been seen at doses ranging from 240 mg Q2W to 800 mg Q4W. 8 of 16 (50%) HR-MDS patients achieved mCR or CR. None of the responding HR-MDS patients has had disease recurrence with exposure durations currently ranging from 3.4 to 18.6 months; two patients in mCR underwent allogeneic stem cell transplant. 4 of 14 (29%) newly diagnosed AML patients have achieved a response of PR or better (2 PR, 2 CR), with 3 additional patients exhibiting ≥ 50% bone marrow blast reduction, and 10 of 14 (71%) continuing on study. 5 of 17 (29%) R/R AML patients have achieved a response of CRi, with 5 additional patients exhibiting ≥ 50% bone marrow blast reduction. Exposure durations for all AML responders currently range from 2.1 to 17.9 months. Median onset of response among all patients was 2.0 months. TIM-3 expression was detected on leukemic cells, with modulation of TIM-3 expression following treatment with decitabine. Conclusions: In this ongoing study in patients with HR-MDS and AML, the combination of MBG453 and decitabine was safe and well tolerated, and exhibited evidence of anti-leukemic activity with encouraging preliminary response rates occurring at a median of 2 cycles, with durability in both HR-MDS and AML. These findings validate TIM-3 as a promising therapeutic target in MDS and AML and support further clinical development of MBG453 in combination with HMAs in patients with MDS and AML. Disclosures Borate: AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Esteve:Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau; Pfizer: Consultancy. Porkka:Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Knapper:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Tolero: Consultancy; Daiichi Sankyo: Honoraria; Pfizer: Consultancy. Vey:Janssen: Honoraria; Novartis: Consultancy, Honoraria. Scholl:Novartis: Other: Project funding; Pfizer: Other: Advisory boards; Gilead: Other: Project funding; AbbVie: Other: Advisory boards; Daiichi Sankyo: Other: Advisory boards. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Wermke:Novartis: Honoraria, Research Funding. Janssen:Amsterdam University Medical Center, location VUmc, Amsterdam, The Netherlands: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Other: Founder of the HematologyApp which is supported by BMS, among others, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Pfizer, among others; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Incyte, among others; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, among others; MSD: Other: Founder of the HematologyApp which is supported by MSD, among others; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Daiichi-Sankyo, among others; Roche: Other: Founder of the HematologyApp which is supported by Roche, among others; Takeda: Other: Founder of the HematologyApp which is supported by Takeda, among others. Traer:AbbVie: Consultancy; Notable Labs: Equity Ownership; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy. Chua:Alfred Hospital, Melbourne, Australia: Employment. Narayan:Takeda: Other: Employment (spouse); Merck: Other: Equity ownership (spouse); Genentech: Other: Equity ownership (spouse). Tovar:Hospital Clinic Barcelona: Employment. Kontro:Amgen: Consultancy; Astellas: Consultancy; AbbVie: Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ottmann:Roche: Honoraria; Pfizer: Honoraria; Fusion Pharma: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Sun:Novartis Institutes for BioMedical Research: Employment; Novartis: Other: Novartis stock owner (stock share as long-term employee incentive). Longmire:Novartis Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Szpakowski:Novartis Institutes for Biomedical Research: Employment, Other: Novartis Stock. Liao:Novartis: Employment. Patel:Novartis Pharmaceuticals: Employment. Rinne:Novartis: Employment; N-Of-One, Inc: Consultancy. Brunner:Astra Zeneca: Research Funding; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Wei:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: MBG453 is an investigational anti-TIM-3 antibody that is being evaluated in hematological malignancies and solid tumors

Background: Pts with higher-risk MDS and AML need treatment options that provide durable responses with sustained clinical benefit and favorable safety/tolerability. Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors but not on normal hematopoietic stem cells. Sabatolimab + HMA has been shown to deliver promising durable responses in a phase (Ph) Ib study in pts with vHR/HR-MDS or newly diagnosed (ND) AML (Wei et al. EHA 2021; NCT03066648). We report updated data from this study, including new analyses evaluating a potential relationship between immune-mediated effects of sabatolimab and response. Final results with additional follow-up will be reported at the time of presentation. Methods: Eligibility criteria and design of this multicenter, open-label study have been previously reported (Wei et al. EHA 2021). The primary objective was to evaluate safety and tolerability. Preliminary efficacy, a key secondary objective, was assessed with overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS) endpoints. Safety and preliminary efficacy are reported for sabatolimab + HMA in pts with vHR/HR-MDS (per IPSS-R) or ND-AML. The proportion of pts who had a possible immune-mediated adverse event (imAE) was evaluated among pts who achieved remission (CR + PR + CRi/mCR) compared with pts that have not achieved remission. The outcomes of pts who received hematopoietic stem cell transplantation (HSCT) after coming off the study were assessed independent of the study by investigators. Results: As of the 15 Jun 2021 data cutoff, 53 pts with vHR/HR-MDS and 48 with ND-AML were treated with sabatolimab + HMA. The combination was safe and well tolerated, with the most common (≥15% in either vHR/HR-MDS or ND-AML) gr ≥3 AEs similar to HMA alone, consisting of thrombocytopenia (43.4%, 45.8%), neutropenia (47.2%, 50.0%), anemia (28.3%, 33.3%), and febrile neutropenia (35.8%, 29.2%), respectively. No pt with vHR/HR-MDS and only 3 with ND-AML discontinued treatment due to an AE regardless of relationship to treatment. In vHR/HR-MDS, 24.5% of pts had improvement allowing them to undergo HSCT. While on study, 6 pts with vHR/HR-MDS and 10 with ND-AML had possible imAEs regardless of relationship to study treatment. Few pts had clinically significant possible imAEs, with no gr ≥3 possible imAEs in pts with vHR/HR-MDS. In ND-AML, 5 pts had gr 3 and none had gr 4/5 possible imAEs. Among 51 pts with vHR/HR-MDS evaluable for response, ORR was 56.9%, with a median DOR (mDOR) of 16.1 mo (Table). The mDOR in pts with CR was 21.5 mo (95% CI, 12.1-NE). Estimated 12-mo PFS rate was 51.9% (95% CI, 30.6%-69.6%). In 40 evaluable pts with ND-AML, ORR was 40.0% and mDOR was 12.6 mo. The mDOR in pts with CR was 23.0 mo (95% CI, 1.3-NE). Estimated 12-mo PFS rate was 27.9% (95% CI, 14.9%-42.5%). Durable responses were also observed in pts with adverse-risk mutations, including TP53 mutations in pts with vHR/HR-MDS (ORR: 71.4% [10/14]; mDOR 21.5 mo [95%CI, 6.7-NE]) and at least 1 ELN adverse-risk mutation (TP53/RUNX1/ASXL1) in pts with ND-AML (ORR: 53.8% [7/13]; mDOR 12.6 mo [95%CI, 1.3-NE]). Although the majority (75%) of pts who went into remission did not experience an imAE, pts in the vHR/HR-MDS cohort who achieved remission more often had a possible imAE (6/24 [25%]) than pts without remission (n=27), none of whom had an imAE. Notably, all 6 pts with vHR/HR-MDS who had an imAE achieved remission. Among pts with ND-AML, the frequency of possible imAEs was similar regardless of remission status. Of the subset of pts who proceeded to HSCT, post-HSCT outcomes in pts with vHR/HR-MDS treated with sabatolimab + HMA were generally favorable without excess toxicities related to graft-versus-host disease. Conclusions: Sabatolimab + HMA was safe and well tolerated and demonstrated durable clinical responses in pts with vHR/HR-MDS and ND-AML. Responses were also durable in pts with adverse-risk mutations. The observed relationship between response and possible imAEs in vHR/HR-MDS would need further confirmation in ongoing studies, but suggests that an immunomodulatory mechanism of sabatolimab may be contributing to clinical responses. The STIMULUS clinical trial program is evaluating sabatolimab-based combination therapy in multiple Ph II and III studies in MDS and AML. Co-senior authors Uma Borate and Andrew H. Wei contributed equally. Figure 1 Figure 1. Disclosures Brunner: Celgene, Forty Seven Inc, Jazz: Other: Advisory Board; Novartis, Celgene, Takeda, AstraZeneca: Research Funding. Esteve: Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Knapper: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Traer: Schrodinger: Research Funding; ImmunoGen: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier/Agios: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Janssen: Uppsala County Council: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Speakers Bureau; Avillion: Research Funding; Ellipses Pharma: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Incyte Biosciences Benelux BV: Research Funding, Speakers Bureau; Glycomimetics: Research Funding. Narayan: Novartis: Research Funding; Sanofi Genzyme: Other: Spouse employment & equity interest; Takeda: Other: Spouse employment & equity interest; Genentech: Other: Spouse employment & equity interest. Kontro: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann: Celgene/BMS: Honoraria, Research Funding; Fusion: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Naidu: Novartis: Current Employment. Pelletier: Novartis: Current Employment. Han: Novartis: Current Employment, Current equity holder in publicly-traded company. Lewandowski: Novartis Institutes: Current Employment. Zhang: Novartis Institutes for BioMedical Research: Current Employment. Mohammed: Novartis: Current Employment. Rinne: Novartis: Current Employment; Qiagen: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Wei: Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Astellas: Honoraria. OffLabel Disclosure: Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3 and is under investigation for the treatment of patients with myeloid malignancies

Background: Sabatolimab (MBG453) is a high-affinity, humanized, IgG4 (S228P) antibody targeting TIM-3, an inhibitory receptor that regulates adaptive and innate immune responses. TIM-3 is expressed on immune cells as well as leukemic stem cells (LSCs) and blasts, but not normal hematopoietic stem cells, making it a promising target in AML/MDS. Sabatolimab is a potential first-in-class immunotherapeutic agent that can target TIM-3 on immune and myeloid cells. Blockade of TIM-3 by sabatolimab may restore immune function while also directly targeting LSCs and blasts. Study Design and Methods : This is a phase Ib, open-label, multicenter, dose-escalation study of sabatolimab + HMA (decitabine [Dec] or azacitidine [Aza]) in patients (pts) with AML or HR-MDS (NCT03066648). Pts were adults with newly diagnosed (ND) or relapsed/refractory (R/R; ≥1 prior therapy) AML or IPSS-R high- or very high-risk MDS; pts with chronic myelomonocytic leukemia (CMML) were also eligible. Pts were HMA naive and ineligible for intensive chemotherapy. Escalating dose cohorts of IV sabatolimab examined were: 240 or 400 mg Q2W (D8, D22) or 800 mg Q4W (D8) combined with Dec (20 mg/m2; IV D1-5) or Aza (75 mg/m2; IV/SC D1-7) per 28-day cycle. Primary objectives included safety/tolerability; secondary objectives included preliminary efficacy and pharmacokinetics. Results: As of the data cutoff (25 Jun 2020), 48 pts with ND AML, 39 pts with HR-MDS, and 12 pts with CMML received sabatolimab + HMA. Data from 29 pts with R/R AML were previously reported. For a broader understanding of the effect of sabatolimab + HMA, results are reported here for the Dec and Aza arms both combined and separately (Table). Median (range) duration of sabatolimab exposure was 4.5 (0.3-28.3) mo for ND AML and 4.1 (0.7-33.6) mo for HR-MDS, with 17 and 11 pts ongoing, respectively. With sabatolimab + HMA, the most common (>10% in either disease cohort) gr ≥3 treatment-emergent adverse events (TEAEs) in pts with ND AML and HR-MDS, respectively, were thrombocytopenia (45.8%, 51.2%), neutropenia (50%, 46.1%), febrile neutropenia (29.2%, 41%), anemia (27.1%, 28.2%), and pneumonia (10.4%, 5.1%). Discontinuation due to AE was infrequent among pts with ND AML (6.3% [3/48]; 1 each of fatigue, febrile neutropenia, and possible HLH); none occurred among pts with HR-MDS. One dose-limiting toxicity occurred with sabatolimab 240 mg Q2W + Dec (gr 3 ALT elevation); the maximum tolerated dose was not reached with either combination. To comprehensively assess possible immune-mediated AEs (imAEs), events were evaluated across all disease cohorts. Seven gr 3 treatment-related possible imAEs were reported in 5 pts: arthritis, rash, possible HLH, and increased ALT in 1 pt each, and hypothyroidism, infusion-related reaction, and increased ALT in 1 pt. No gr 4 treatment-related possible imAEs occurred; however, there was a case of enterocolitis in a pt with HR-MDS who died of septic shock with neutropenic colitis. No other treatment-related deaths were reported. Among 34 evaluable pts with ND AML, overall response rate (ORR) was 41.2%: 8 CR, 3 CRi, 3 PR. Median (range) time to response (TTR) was 2.1 (1.8-13.1) mo and estimated 6-mo duration of response (DOR) rate was 85.1% (95% CI: 68-100%). Estimated 12-mo progression-free survival (PFS) rate was 44% (95% CI: 28-69.3%). Among 35 evaluable pts with HR-MDS, ORR was 62.9%: 8 CR, 8 mCR (5 with hematologic improvement [HI]), 6 SD with HI. Median (range) TTR was 2.0 (1.7-9.6) mo and estimated 6-mo DOR rate for CR/mCR/PR was 90% (95% CI: 73.2-100%). Encouraging response rates were achieved in both pts with high-risk MDS (ORR 50% [11/22]) and very high-risk MDS (ORR 84.6% [11/13]). Of pts with HR-MDS, 8 (5 high-risk, 3 very high-risk) proceeded to transplant. Estimated 12-mo PFS rate was 58.1% (95% CI: 39.9-84.6%). Among 12 pts with CMML, the safety profile of sabatolimab + HMA was generally consistent with that for AML/HR-MDS (most common gr ≥3 TEAEs: thrombocytopenia, n=7; neutropenia, n=7; anemia, n=6). ORR among 11 evaluable pts was 63.6%: 2 CR, 3 mCR, 1 PR, 1 SD with HI. Conclusions: Sabatolimab + HMA is well tolerated in pts with AML and HR-MDS and continues to show promising antileukemic activity and emerging durability. These results support TIM-3 as a potential therapeutic target and provide a basis for further development of sabatolimab + HMA in pts with AML or higher-risk MDS. Co-senior authors Uma Borate and Andrew H. Wei contributed equally to the work. Table Disclosures Brunner: Acceleron Pharma Inc.: Consultancy; Biogen: Consultancy; Celgene/BMS: Consultancy, Research Funding; Forty Seven, Inc: Consultancy; Jazz Pharma: Consultancy; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Xcenda: Consultancy; GSK: Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding. Porkka:Novartis: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria, Research Funding. Knapper:Novartis: Consultancy, Honoraria, Research Funding. Garcia-Manero:Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding. Wermke:MacroGenics: Honoraria. Janssen:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Takeda: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Roche: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; MSD: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda. Traer:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Notable Labs: Consultancy, Current equity holder in private company; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Narayan:Sanofi-Genzyme: Other: Current Spouse employment ; Takeda: Other: Prior Spouse employment within 24 months; Genentech: Other: Prior Spouse employment within 24 months and prior spouse equity divested within past 24 months. Kontro:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Ottmann:Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Fusion Pharma: Honoraria; Incyte: Honoraria, Research Funding. Naidu:Novartis Pharmaceuticals: Current Employment. Kurtulus:Novartis: Current Employment. Makofske:Novartis: Current Employment. Liao:Novartis: Current Employment. Sabatos-Peyton:Novartis: Current Employment, Patents & Royalties: Yes, patent related to MBG453 and also prior TIM-3 patents from grad student/ postdoc work at Harvard/BWH; CoStim Pharmaceuticals: Patents & Royalties: Held shares as employee, now paid via Novartis. Rinne:Qiagen: Consultancy; Novartis: Current Employment. Borate:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Jazz Pharmaceuticals: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Wei:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding.

Glucocorticoids (GCs) are metabolic hormones with immunosuppressive effects that have proven effective drugs against childhood acute lymphoblastic leukemia (ALL). Yet, the role of metabolic reprogramming in GC-induced ALL cell death is poorly understood. GCs efficiently block glucose uptake and metabolism in ALL cells, but this does not fully explain the observed induction of autophagy and cell death. Here, we have performed parallel time-course proteomics, metabolomics, and isotope-tracing studies to examine in detail the metabolic effects of GCs on ALL cells. We observed metabolic events associated with growth arrest, autophagy, and catabolism prior to onset of apoptosis: nucleotide de novo synthesis was reduced, while certain nucleobases accumulated; polyamine synthesis was inhibited; and phosphatidylcholine synthesis was induced. GCs suppressed not only glycolysis but also entry of both glucose and glutamine into the TCA cycle. In contrast, expression of glutamine-ammonia ligase (GLUL) and cellular glutamine content was robustly increased by GC treatment, suggesting induction of glutamine synthesis, similar to nutrient-starved muscle. Modulating medium glutamine and dimethyl-α-ketoglutarate (dm-αkg) to favor glutamine synthesis reduced autophagosome content of ALL cells, and dm-αkg also rescued cell viability. These data suggest that glutamine synthesis affects autophagy and possibly onset of cell death in response to GCs, which should be further explored to understand mechanism of action and possible sources of resistance.