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Abstract Introduction According to population-based Surveillance, Epidemiology and End Results (SEER) cancer registry data, approximately 40% of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) in the United States (U.S.) are Hispanic and 7% are Black and both Hispanic and Black patients have significantly inferior outcomes relative to non-Hispanic Whites (NHW). CALGB 10403, a prospective Phase II clinical trial conducted by the U.S. Intergroup, demonstrated the feasibility of delivering a pediatric-inspired ALL regimen to newly diagnosed AYA ALL patients and found this approach to be superior to historical adult regimens (Stock et al. Blood 2019). In the current analysis, we evaluate enrollment patterns of Hispanic and Black AYAs on CALGB 10403 and compare survival relative to SEER estimates. Methods Demographics on AYAs (18-40 yrs) enrolled on CALGB 10403 (N=295 from 2007-2012) were supplemented with patient-reported education and socioeconomic status (SES) information. Data from the North American Association of Cancer Registries (NAACCR; 2013-2017) were used to evaluate U.S. country-wide ALL incidence (20-49 yrs) overall and among Hispanics, reported per U.S. state. SEER registries (2008-2012) provided racial/ethnic distribution and overall survival (OS) of AYA ALL (15-39 yrs). The distribution of OS was estimated using the Kaplan-Meier method and compared across racial/ethnic groups using log-rank tests. Results Relative to the U.S. AYA ALL population, CALGB 10403 included proportionally fewer Hispanics (41.7% vs. 16.3%, P < 0.001); the distribution of blacks was similar (6.4% vs. 8.5%, P = 0.174). Demographics and ALL characteristics among CALGB 10403 enrollees demonstrated no significant differences in age, sex, cytogenetics, or BMI by race/ethnicity; however, Black AYAs were more likely to have T-ALL, and Hispanic patients were more likely to have Ph-like B-ALL and rearrangements in CRLF2. Hispanic and Black patients reported lower household yearly income, and Black patients had less educational attainment. In order to explore reasons for disproportionately low Hispanic enrollment on CALGB 10403, we calculated the proportion of Hispanic AYAs with ALL relative to the AYA ALL incidence across U.S. states using NAACCR data and compared this with the geographical distribution of CALGB 10403 enrollments. The incidence of AYA ALL across U.S. states is represented in Fig 1A and the proportion of Hispanic AYA ALL patients in Fig 1B. The states with highest proportion of Hispanic patients included CA, TX, and NM, followed by AZ, CO, FL, and NJ. Although CALGB 10403 enrolled patients in 31 U.S. states, the trial did not open in TX or FL. The enrollments numbers were highest across the Mid-Western U.S., with only 47/295 (15.9%) of enrollments coming from the seven states with a high proportion of Hispanic AYA ALL patients (Fig 1C). The 3-yr event-free survival (EFS) and OS for the total CALGB 10403 cohort were 59.1% (53.1%, 65.75%) and 73.5% (68.1%, 79.4%), respectively. Per protocol completion of therapy was highest in Hispanics (75%), relative to Black (64%) and NHW patients (56%), P=0.049. Overall survival among CALGB 10403 participants differed significantly across race/ethnicity (Fig 2), with superior OS experienced by Hispanic patients and inferior OS by Black patients (P= 0.021). These clinical trial results differ from SEER estimates, where both Hispanic and Black patients experience worse OS relative to NHW (Fig 2). Conclusions This in-depth analysis of racial/ethnic enrollments and outcomes on CALGB 10403 uncovered findings that may translate across clinical trials beyond AYA ALL. Importantly, our data suggest that closer matching of trial site selection to geographical racial/ethnic disease incidence may improve minority enrollments on multi-center clinical trials. Relative to NHW, Hispanic patients had superior survival despite having higher rates of Ph-like ALL, indicating that clinical trial participation may mitigate racial/ethnic survival disparities seen in population-based data. Finally, we saw no improvement in trial outcomes among Black AYAs; a deeper understanding of the biological leukemia underpinnings and barriers to successful outcomes would aid future efforts at improving survival across racial/ethnic groups. Figure 1 Figure 1. Disclosures Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Advani: Abbvie: Research Funding; Macrogenics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; OBI: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Tallman: NYU Grand Rounds: Honoraria; Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Foster: Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bellicum Pharmaceuticals: Research Funding. Larson: Gilead: Research Funding; Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Rafael Pharmaceuticals: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Cellectis: Research Funding.

Abstract Introduction: Allogeneic stem cell transplantation (alloSCT) is the most effective post remission anti-leukemia strategy. However, the associated toxicity is a barrier for its routine adoption as standard of care in older adults. Studies of AML patients who underwent alloSCT are mainly retrospective as randomized controlled trials comparing transplantation to non-transplantation are very difficult to conduct. We herein present prospective data from a randomized controlled phase III study, E2906, designed to compare two intensive chemotherapy arms. Patients who achieved remission and had a donor were to proceed to alloSCT after induction or first consolidation, at investigator discretion. Non-transplanted patients received 2 cycles of consolidation and then underwent a second randomization between observation and decitabine maintenance. Herein are reported all patients who received alloSCT either on protocol during first remission (CR1) or at other post induction time-points. Patients and Methods: Enrolled to E2906 study were 727 AML patients age 60 years and over. AlloSCT was performed in 166 patients, of whom 71 received alloSCT as part of the study and 95 received alloSCT off protocol. 105 patients (66/71 on protocol, 39/95 off protocol) received alloSCT at CR1/CRi1/LFS1 (CR: 92, CRi: 9 LFS: 4). Patients were followed for a median of 33.6 months from diagnosis and 29.1 months from transplant. No patients received decitabine maintenance prior to alloSCT. Overall survival (OS) is defined as the time from allo transplant to death from any cause, with follow-up censored at the date of last contact. Disease free survival (DFS) is defined as the time from alloSCT transplant to relapse or death of any cause. The censored follow-up time for patients without relapse or death information is the date of last contact. Kaplan-Meier estimates were used to estimate OS and DFS. DFS and OS were compared between subgroups using log rank tests. A cumulative incidence analysis, with death without prior relapse as competing events, was performed to evaluate the subgroup effect on time to relapse after transplant. Results: Patient characteristics of those who received alloSCT at CR1/CRi1/LFS1 are similar to the general distribution of AML patients eligible for intensive chemotherapy. Median age was 66 years, 52% were male and 88% with ECOG PS of 0-1. Cytogenetic data were available for 85 patients of whom 26% presented with unfavorable cytogenetics. Minimal residual disease (MRD) status prior to alloSCT was available for 44 patients of whom 19 (43%) achieved a MRD negative state. Long-term OS and DFS rates for all 105 patients who underwent alloSCT at CR1/CRi1/LFS1 are encouraging (Figure 1). OS and DFS at two years were 56.4% and 53.6% and 49.4%, 45.6% and 42.9%, 39% at 3 and 4 years, respectively. Age above or below 65 years, gender, induction regimen (3+7 or clofarabine) and MRD status prior to transplantation had no impact on outcome. Survival curves by intermediate or adverse cytogenetic risk are not significantly different. The numbers of patients with CRi1 or LFS1 are too small to compare with patients in CR1. Nevertheless, 36/38 patients that were alive and remain in first remission at the time of data cutoff, are patients who achieved CR1 and only 2/38 are patients transplanted at CRi1 or LFS1. Notably, the non-relapse mortality (NRM) was not significantly different for patients less or over 65 years. NRM at 6 months and 2 years for patients over and under 65 years of age were 4.4%, 8.4% and 15.6%, 24.0% respectively. Relapse during the first year post alloSCT is the main barrier for longer survival, particularly in patients with adverse cytogenetics and MRD positivity prior to transplantation (Figure 2). Conclusions: Fit older patients, including those over age 65, who undergo an alloSCT in CR1, can expect a 4-year survival of 43% with an acceptable NRM rate. The NRM was, surprisingly, not higher than for a typically younger cohort of AML. Relapse within one year after transplant is the major limitation to prolonged survival and this finding reflects the biology of the leukemia in these patients. In this patient population, novel post remission strategies should either be complimentary to alloSCT or competitive with updated outcome of alloSCT. Figure 1 Figure 1. Disclosures Ofran: Medison Israel: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Astellas: Consultancy; AbbVie: Consultancy. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; NYU Grand Rounds: Honoraria; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Melnick: Constellation: Consultancy; Epizyme: Consultancy; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceuticals: Research Funding; KDAC Pharma: Membership on an entity's Board of Directors or advisory committees. Levine: Prelude: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Lilly: Honoraria; Morphosys: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Astellas: Consultancy; Imago: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Research Funding; Roche: Honoraria, Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Foran: gamida: Honoraria; aptose: Research Funding; syros: Honoraria; boehringer ingelheim: Research Funding; kura: Research Funding; takeda: Research Funding; abbvie: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; certara: Honoraria; actinium: Research Funding; OncLive: Honoraria; pfizer: Honoraria; servier: Honoraria; bms: Honoraria; novartis: Honoraria; taiho: Honoraria; sanofi aventis: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Jazz: Other: Advisory Board; AbbVie: Research Funding; Omeros: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee.

Abstract Background: Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remain a therapeutic challenge, especially in elderly patients(pts) or those with T-cell immunophenotype. Inhibition of apoptosis is an increasingly recognized mechanism for resistance to conventional chemotherapy. Recently, the oral bcl-2 inhibitor venetoclax (VEN) has shown remarkable activity in a variety of hematologic malignancies. Preclinical data in both B- and T-ALL suggests synergy of VEN with vincristine(VCR). Liposomal VCR (L-VCR) is FDA approved for relapsed ALL having progressed following 2 or more antileukemia therapies. We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for pts with r/r B-or T-cell ALL or LL. Here, we report for the first time the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). Methods: This open-label phase I/II study enrolled pts age>=18 with ALL or LL who were R/R to multiagent chemotherapy. Subjects could have received prior VCR or VEN . In a standard 3 + 3 dose escalation design, subjects were given a two week lead-in phase of single agent VEN in the following schedule: dose level 1 - 20, 50, 100, 200 mg on days 1, 2, 3, 4 and 400 mg on days 5 ‒ 42; dose level 2 - 50, 100, 200, 400 mg on days 1, 2, 3, 4 and 600 mg on days 5 ‒ 42; and dose level 3 ‒ 100, 200, 400, 600 mg on days 1, 2, 3, 4 and 800 mg on days 5 ‒ 42. Weekly L-VCR 2.25mg/m 2 IV was started on D15 of cycle 1, and starting day 1 for subsequent cycles (cycle 2+ = 28 days). For cycle 2 and beyond, VEN 400mg, 600mg, or 800mg based on dose level was given starting on day 1 of the cycle. Primary objective of the phase I portion was to determine the maximum tolerated dose (MTD) of VEN in combination with L-VCR. Secondary objectives included determining preliminary response rates. Results: EA9152 was activated on April 26, 2018 and the phase I portion closed to accrual on March 2, 2021. Among the 18 pts in dose escalation (Table 1), the median age was 42 years (22-77). The majority of pts were male (56%), white (80%), and with a performance status (PS) of 1 (78%). Among 13 pts with disease diagnosis reported, 9 had ALL and 4 had LL. Seventeen of 18 (94%) reported previous chemotherapy, two of which had previous stem cell transplant. Median treatment cycles received is 1 (range 1-11). One patient, having received 11 cycles, remains on study at the time of data analysis. Grade >=3 treatment-related adverse events were reported in 89% of treated pts, with neutrophil count decreased (67%), white blood cell decreased (56%), and anemia (50%) as the most common. One pt experienced grade 3 tumor lysis syndrome. Twelve pts were considered evaluable for MTD determination. Six pts were considered not evaluable for toxicity analysis on account of withdraw of consent for treatment (n=4) or rapid disease progression (n=2). Two pts (2 of 3) at dose level 3 experienced DLTs, one each of hypokalemia and heart failure. Therefore, the MTD of the combination was determined to be dose level 2 - VEN 50, 100, 200, 400 mg on days 1, 2, 3, 4 and 600 mg on days 5 ‒ 42 and for subsequent cycles, with L-VCR 2.25mg/m2 IV weekly. In regards to best overall responses observed (Table 2) 4 of 18 pts (22%) achieved complete response (CR), 4 patients (22%) had stable disease, and 7 (39%) had progressive disease. Two patients in CR were found to be measurable residual disease (MRD) negative as well. Conclusions: In the phase 1 portion of this study, the combination of VEN and L-VCR was found to be safe for patients with ALL and LL. The MTD of the combination was found to be VEN 600mg daily with encouraging preliminary efficacy seen including MRD negative responses. The phase 2 portion of this trial is actively enrolling with VEN 600mg daily starting C1D1. Figure 1 Figure 1. Disclosures Palmisiano: Takeda: Consultancy; Genentech: Research Funding; Foundation One: Consultancy; AbbVie: Consultancy, Research Funding. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding. Park: BMS: Consultancy; Amgen: Consultancy; Autolus: Consultancy; Novartis: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Kura Oncology: Consultancy; Affyimmune: Consultancy; Servier: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy. Podoltsev: Novartis: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Blueprint Medicines: Honoraria; Bristol-Myers Squib: Honoraria; PharmaEssentia: Honoraria; CTI BioPharma: Honoraria. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Webster: AmGen: Consultancy; Pfizer: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. OffLabel Disclosure: Venetoclax, a BCL-2 inihibitor, is not FDA-approved for use in ALL.

Abstract Introduction Several studies reported that AML patients who remain in long-term remission after allogeneic transplant (allo-HCT) or autologous transplant (auto-HCT) have a shorter life expectancy, compared to the general population. However, little is known about the life expectancy of adult long-term survivors of AML who were treated with chemotherapy without HCT and, there have been no comparisons with survival among the general population. The current study reports on the life expectancy of AML patients who survived 3 years in complete remission (CR) after treatment without HCT, and compared this to the gender- and age-matched normal population. At 3 years in CR, the incidence of recurrence is exceedingly low (3%; Watts JM, Leuk Res 2014) minimizing the impact of relapse on the long-term survival. Methods Between 1984 and 2008, 3,012 patients, aged 15 years and older, with untreated AML entered 9 consecutive, phase II and III, ECOG-ACRIN trials (E3483, PC486, E3489, E1490, E3993, E4995, E3997, E3999, E1900). Patients in CR and relapse-free at 3 years are included in the analysis . Minimal cytogenetic information was available in the early protocols (E1490, E3483, PC486). A Kaplan-Meier plot was generated for the three groups, allo, auto and no HCT, censoring for patients alive at last contact. Univariate and multivariate cox proportional hazard regression models were generated, considering death as an event. For comparison of long-term outcomes, patients were grouped together by age and matched to a normative population mortality rate. Subjects were also grouped by gender and treatment allowing for separate analysis of these groups with the no HCT group as the main group of interest. The normative population comparator of expected deaths was derived using mortality rates from United State CDC life table data. The median year was derived by calculating the person-years for each calendar year that patients were followed. To calculate the expected deaths for each age group, person-years was calculated by tabulating the years lived in each age group for all subjects. Each year of follow-up for AML patient was counted as one person year, and the tabulated bin corresponded with their age at the time. Person-years was then multiplied by the matching mortality rate. Chi-square statistics were derived using expected and observed deaths and then summed for each gender and treatment. The final comparison was of mortality rates since diagnosis in the 3-year alive and relapse-free AML patient population vs the normative population. To produce plots of mortality from diagnosis, person-years was tabulated for every year since diagnosis by treatment. The person-years were tabulated into 2-year bins. The US life tables from the CDC were used to generate a population mortality rate from diagnosis. Results A total of 503 adult AML patients in 3 year CR with a mean age of 42.9 years (15-79) were identified; 78 underwent allo, 110 auto and 315 did not undergo transplantation. The patients in the groups differed in age (p<.001) and cytogenetics (p=.01). The multivariate model showed equivalent hazards of death to the 3 groups. Observed deaths and person-years were given by age group, gender, and treatment group and each were matched to a mortality rate from the United State CDC life table data that matched the median year of each treatment group. A chi square test for each group compared the derived expected to observed deaths. In every treatment group, patients had a shorter survival compared to their age- and gender- matched general population (p-value of 0.004 for the auto-HCT and <0.001 for both allo-HSCT and no transplant groups). Table 1, selected only for the no HCT group, demonstrates the mortality rates by age and gender. Figure 1 indicates that AML patients who have survived relapse-free for at least 3 years continue to have higher mortality rates compared to the normative population for up to 14 years. This finding is not altered even if the very small number of patients who die from late relapse (>3 years from diagnosis) are removed from the analysis (data not shown) Conclusions Patients with AML who remain in CR at 3 years, do not have a normal life expectancy, even if they do not undergo HCT. The shorter life expectancy observed following an HCT may, at least in part, be related to the prior intensive therapy or other predisposing factors (e.g. CHIP) of the leukemia, rather than the transplant procedure itself. Figure 1 Figure 1. Disclosures Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Douer: Amgen: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy. Tallman: Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; NYU Grand Rounds: Honoraria; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Pluristem: Research Funding; Biosight: Other: Data monitoring committee; AbbVie: Research Funding; Actinium: Research Funding; Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding.

Abstract Background: CML is managed by life-long TKI therapy in most pts which can be associated with chronic toxicities and substantial costs. Discontinuation of TKI in some pts can result in sustained therapy-free remission (TFR); however only a minority are candidates for discontinuation approaches; of those most still relapse and must restart TKI. High expression of programmed death receptor-1 (PD-1) and its ligand PD-L1 on CML-specific cytotoxic T-cells and CML cells, respectively, suggests that PD-1/PD-L1-mediated immune escape contribute to CML persistence and relapse after TKI discontinuation. We designed the BLAST MRD CML trial (NCT#03516279) to study whether adding anti-PD-1 antibody pembrolizumab to TKI therapy is safe and tolerable and increases rate of conversion to undetectable minimal residual disease (UMRD). We present data from the early safety cohort from this ongoing trial with a data cut-off date June 15th, 2021. Methods: BLAST MRD CML-1 is an ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial that enrolls adults with chronic phase CML who achieved a major molecular response (MR 3) but not UMRD while on a stable dose of up to three lines of TKI therapy. UMRD was defined as an undetectable BCR-ABL by central RQ-PCR (assay sensitivity of 4.5 [MR 4.5]) on 2 consecutive samples separated by ≥4 weeks. Once enrolled, pts continue on TKI and concurrently receive pembrolizumab 200mg IV on day (D)1 of each 21-D cycle with central MRD assessment every 4 cycles for 17 cycles. Pts who achieve UMRD at or prior to C17 discontinue pembrolizumab, while those with persistent MRD continue TKI + pembrolizumab for another 18 cycles. TKI is discontinued one year following first documentation of UMRD. After TKI discontinuation, BCR-ABL is monitored at defined intervals for 24 months. Primary endpoint is proportion of CML pts on stable-dose TKI who convert to UMRD within 2 years (yrs) of combined TKI + pembrolizumab therapy. Secondary endpoints include rates of TKI discontinuation and proportion of pts achieving 2-year TFR, MRD kinetics, and safety. Immune related and other adverse events (AE) were assessed and graded according to CTCAE v 5.0. Results: As of cut-off date, 6 pts enrolled in safety cohort. Median age was 43 yrs (range 32-65). TKIs received on trial included imatinib (N=2), dasatinib (N=3), and nilotinib (N=1). All 6 pts were on 2 nd line TKI. Median exposure to pembrolizumab was 20 doses (range, 5-36). Five pts were still on combined pembrolizumab + TKI treatment, while the 6 th pt has completed combined therapy for 2 yrs and then continued TKI monotherapy on trial after achievement of UMRD (pt has to be in UMRD for 1 yr before TKI can be discontinued). The combination of TKI and pembrolizumab was safe and well tolerated (Table 1). Only 3 pts experienced grade (G) 1/2 AEs as the worst non-hematologic AE while on trial. Hematologic toxicity reported was also generally minimal with only one G 1/2 anemia AE. The only reported G3 AE was a lipase elevation (283 U/L, normal range 11 - 55 U/L) noted on routine laboratory assessment in a pt receiving nilotinib at 400mg BID dose after 48 weeks of starting on trial combined therapy. Amylase was also elevated at G2. No baseline lipase levels were available as protocol at that time did not require baseline assessments. The pt had no symptoms and CT imaging showed no radiologic evidence of pancreatitis. The lipase and amylase levels normalized with holding of both nilotinib and pembrolizumab for 7 weeks, and the AE did not recur with resumption of combined therapy at same dose of pembrolizumab but with nilotinib reduced to 400mg daily. No G4 or 5 AEs occurred. No other dose-adjustments or treatment discontinuation/interruptions due to AEs occurred. No immune-related AEs (IRAEs) have been reported. Discussion: Data from the early safety cohort suggest that the combination of TKI and pembrolizumab is safe and well tolerated. The AEs observed were mild and generally G1/2. No pt discontinued trial therapy due to AEs. Only one G3 AE (asymptomatic lipase elevation) was reported, which could have been related to nilotinib therapy and could have predated trial entry as no baseline lipase value was available and was fully reversible with a temporary hold of therapy. No IRAEs have been reported to date. Work is ongoing on an amendment to study protocol to enhance accrual. Efficacy results will be reported as they mature. Figure 1 Figure 1. Disclosures Zeidan: Boehringer Ingelheim: Consultancy, Research Funding; Ionis: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Astex: Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BeyondSpring: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BioCryst: Other: Clinical Trial Committees; Janssen: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Geron: Other: Clinical Trial Committees; Astellas: Consultancy; ADC Therapeutics: Research Funding; Agios: Consultancy; Jazz: Consultancy; Pfizer: Other: Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bhatt: National Marrow Donor Program: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Research Funding; Jazz: Research Funding; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: Omeros: Other: Advisory Board; Astellas: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Pembrolizumab has not been approved for the treatment of CML

Abstract Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. However, current SMM risk models rely solely on clinical markers and do not accurately capture progression risk. While incorporating some genomic biomarkers improves prediction, using all MM genomic features to comprehensively stratify patients may increase risk stratification precision in SMM. Methods: We obtained a total of 214 patient samples at SMM diagnosis. We performed whole-exome sequencing on 166 tumors; of these, RNA sequencing was performed on 100. Targeted capture was done on 48 additional tumors. Upon binarization of DNA features, we performed consensus non-negative matrix factorization to identify distinct molecular clusters. We then trained a random forest classifier on translocations, SNVs, and CNVs. The predicted clinical outcomes for the molecular subtypes were further validated in an independent SMM cohort of 74 patients. Results: We identified six genomic subtypes, four with hyperdiploidy (>48 chromosomes, HMC, HKR, HNT, HNF) and two with IgH translocations (FMD, CND) (Table 1). In multivariate analysis accounting for IMWG (20-2-20) clinical risk stages, high-risk (HMC, FMD, HKR) and intermediate-risk (HNT, HNF) genetic subtypes were independent predictors of progression (Hazards ratio [HR]: 3.8 and 5.5, P = 0.016 and 0.001, respectively). The low-risk, CND subtype harboring translocation (11;14) was enriched for the previously defined CD-2 MM signature defined by the B cell markers CD20 and CD79A (FDR = 0.003 ), showed upregulation of CCND1, E2F1, and E2F7 (FDR = 0.01, 0.0004, 0.08), and was enriched for G2M checkpoint, heme metabolism, and monocyte cell signature (FDR = 0.003, 0.003, 0.003, respectively). The FMD subtype with IgH translocations (4;14) and (14;16) was enriched for P53, mTORC1, unfolded protein signaling pathways and plasmacytoid dendritic cell signatures (FDR = 0.01, 0.005, 0.008, respectively). The HKR tumors were enriched for inflammatory cytokine signaling, MYC target genes, T regulatory cell signature, and the MM proliferative (PR) signatures (FDR = 0.02, 0.03, 0.007, 0.02, respectively). The APOBEC mutational signature was enriched in HMC and FMD tumors (P = 0.005), while there was no statistical difference across subtypes in the AID signature. The median follow-up for the primary cohort is 7.1 years. Median TTP for patients in HMC, FMD, and HKR was 3.8, 2.6, and 2.2 years, respectively; TTP for HNT and HNF was 4.3 and 5.2, respectively, while it was 11 years in CND patients (P = 0.007). Moreover, by analyzing the changes in MM clinical biomarkers over time, we found that patients from high-risk subgroups had higher odds of developing evolving hemoglobin and monoclonal protein levels over time (P = 0.01 and 0.002, respectively); Moreover, the absolute increase in M-protein was significantly higher in patients from the high-risk genetic subtypes at one, two, and five years from diagnosis (P = 0.001, 0.03, and 0,01, respectively). Applying the classifier to the external cohort replicated our findings where intermediate and high-risk genetic subgroups conferred increased risk of progression to MM in multivariate analysis after accounting for IMWG staging (HR: 5.5 and 9.8, P = 0.04 and 0.005, respectively). Interestingly, within the intermediate-risk clinical group in the primary cohort, patients in the high-risk genetic subgroups had increased risk of progression (HR: 5.2, 95% CI 1.5 - 17.3, P = 0.007). In the validation cohort, these patients also had an increased risk of progression to MM (HR: 6.7, 95% CI 1.2 - 38.3, P = 0.03), indicating that molecular classification improves the clinical risk-stratification models. Conclusion: We identified and validated in an independent dataset six SMM molecular subgroups with distinct DNA alterations, transcriptional profiles, dysregulated pathways, and risks of progression to active MM. Our results underscore the importance of molecular classification in addition to clinical evaluation in better identifying high-risk SMM patients. Moreover, these subgroups may be used to identify tumor vulnerabilities and target them with precision medicine efforts. Figure 1 Figure 1. Disclosures Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Casneuf: Janssen: Current Employment. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Davies: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria. Bergsagel: Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Yong: BMS: Research Funding; Autolus: Research Funding; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

Abstract Background: Hypomethylating agents (HMA) are well established standard of care for patients (pts) with higher-risk MDS (HR-MDS). However, approximately half of the pts do not respond to HMA therapy and most of the responders eventually lose response (HMA failure). There is no standard of care for pts after HMA failure and median overall survival (OS) post HMA failure is around 6 months (Jabbour et al. 2015). While the mutational landscapes and their role in prognosis are increasingly becoming apparent in pts with HR-MDS at diagnosis, mutational profiles at the time of HMA failure and their impact on clinical outcomes are not well understood. Here, using samples collected from a global Phase 3 trial randomizing HR-MDS pts post HMA failure to I.V. rigosertib (RGS) or physician's choice (PC) (INSPIRE: NCT02562443), we analyzed the landscape of driver mutations in HR-MDS after HMA failure and investigated the association with the clinical outcomes. Since RGS is a non-ATP-competitive small molecule RAS mimetic (Athuluri-Divakar 2016), the study also offered an opportunity to test the hypothesis whether HR-MDS pts with oncogenic RAS pathway mutations benefit from RGS. Methods: HR-MDS pts after HMA failure were randomized 2:1 to RGS or PC. All pts failed to respond to or progressed on prior HMA therapy. Bone marrow samples or peripheral blood samples were collected at the time of trial screening. Genomic DNA was sequenced by the targeted capture deep sequencing of 295 genes (median 500x). Results: 372 pts were enrolled in INSPIRE trial (248 to RGS and 124 to PC). The median age of the trial participants was 73 (range: 40-85). All pts were previously treated and with an HMA with the median duration of prior HMA therapy of 6.7 months. 64% and 28% of the pts were classified as IPSS-R very high risk or high risk, respectively, at the time of randomization. Among the 372 participants, DNA sequencing of pre-treatment samples was performed in 188 pts (51% of the participants, N = 122 in RGS arm, N = 66 in PC arm). The most frequently identified driver mutations involved ASXL1 (36%) followed by RUNX1 (24%), TET2 (23%), STAG2 (22%) and TP53 (21%). Mutations in splicing pathway genes were found in 36% of the pts. Oncogenic RAS pathway mutations were detected in 15% of the pts (NRAS = 3 %, KRAS = 2%, CBL = 4%, NF1 = 5%, PTPN11 = 3%, and 1% had multi-hit mutations). Compared to the previously untreated MDS pts (N = 446, Papaemmanuil et al. Blood 2013), mutations in ASXL1 (36% vs. 18%, P < 0.0001), BCOR (9% vs. 3%, P = 0.002), CEBPA (4% vs. 0.2%, P = 0.001), NF1 (5% vs. 0.9%, P = 0.003), RUNX1 (25% vs. 11%, P < 0.0001), STAG2 (22% vs. 5%, P < 0.0001), TP53 (21% vs. 6%, P < 0.0001), and IDH1/2 (13% vs. 7%, P =0.016) were significantly more enriched in pts with HMA failure, whereas mutations in SF3B1 (7% vs. 37%, P < 0.0001), TET2 (23% vs. 35%, P = 0.006), and splicing pathway genes (36% vs. 68%, P < 0.0001) were significantly less frequent in HMA failure pts. These results are consistent with the high-risk profiles of HMA failure pts. Frequency of oncogenic RAS pathway mutations were similar between HMA failure and previously untreated MDS pts (15% vs. 13%, P = 0.612). Correlation analysis between the types of HMA failure and gene mutations showed that TP53 mutations were significantly enriched in pts who relapsed after initial response to HMA (P = 0.001), whereas oncogenic RAS pathway mutations were significantly enriched in pts who progressed during the HMA therapy (P = 0.03). Overall, RGS did not significantly improve the overall survival (OS) of HMA failure pts compared to PC. Survival difference between RGS arm and PC arm was not observed in any subgroups stratified by the gene mutations. The only subgroup that showed improved OS with RGS compared to PC was pts with RAEB-t (median OS 7.5 vs. 3.9 months, P = 0.049). Of note, among pts with oncogenic RAS pathway mutations, no survival difference was observed between RGS and PC arms. Conclusion: High-risk gene mutations, such as TP53, ASXL1, RUNX1, and STAG2 (Ogawa. Blood 2019). were significantly enriched in MDS pts with HMA failure, suggesting their role in HMA resistance and disease progression. Identifying the mutations present de novo and with HMA failure offers the opportunity to determine prognosis based on these mutations as well as potential strategies to target these mutations with new medical entities. Disclosures Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Diez-Campelo: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Rigosertib for MDS patients after HMA failure

Abstract Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia or lymphoma (T-ALL or T-LBL respectively) and acute myeloid leukemia (AML) have remained poor despite the availability of newer agents. CD38 is a 45 kDa transmembrane glycoprotein expressed by lymphoid and myeloid cells with several important functions including a role in immune escape from tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in tumor cells of patients with T-ALL and AML and potentially targetable using CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020, Farber M et al. ASH 2018]. XmAb18968 is structurally distinct CD3-CD38 bi-specific T-cell engager with a full fragment crystallizable (Fc) domain modified to minimize Fcγ receptor binding and non-selective activation of T cells and other immune effector cells. XmAb18968 has optimized relative affinities for both CD3 and CD38 which results in reduced cytokine release without compromising target cell killing. We hypothesize targeting CD38 in relapsed/refractory- T-cell ALL/LBL and AML is safe and feasible using XmAb18968, a novel CD3-CD38 bispecific antibody. Study design and methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with T-ALL, T-LBL or AML (including undifferentiated leukemia and bi phenotypic leukemia), in relapsed/refractory status (at least one line of prior therapy) including measurable residual disease relapse, CD38 expression ≥ 20%, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation (HCT) within 6 months of enrollment, active acute GVHD, veno-occlusive disease, and acute promyelocytic leukemia. The study is planned to be conducted at 6 sites in United States. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of responses with genomic profile, assessment of serum cytokine response, identifying the changes in phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design for dose escalation and de-escalation in case of dose limiting toxicity (DLT). Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and T-LBL and Group B for subjects with AML. Patients will be entered sequentially to each dose level, starting with the first dose level. The DLT observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experience a DLT. A minimum of 24 and a maximum of 60 patients will be needed for the dose escalation phase. Disclosures Guru Murthy: Curio Sciences: Honoraria; Techspert: Consultancy; Qessential: Honoraria; CancerExpertNow: Honoraria; DAVA Oncology: Honoraria; TG Therapeutics: Other: Advisory board meeting; Cardinal health: Honoraria; Guidepoint: Consultancy. Johnson: Miltenyi Biotec: Research Funding. Abedin: AltruBio: Research Funding; Amgen: Honoraria; Agios: Honoraria; Helsinn: Research Funding; Pfizer: Research Funding; Astellas Pharma Inc.: Research Funding; Actinium: Research Funding. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Shah: Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Leonard: Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Pratz: Agios: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding; University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Pfizer: Consultancy, Research Funding.

Abstract Early T-cell acute lymphoblastic leukemia (ETP-ALL) is an aggressive hematologic malignancy associated with early relapse and poor prognosis that is genetically, immunophenotypically, and transcriptionally distinct from more mature T-cell acute lymphoblastic leukemia (T-ALL) tumors. Here, we leveraged global metabolomic and transcriptomic profiling of primary ETP- and T-ALL leukemia samples to identify specific metabolic circuitries differentially active in this high-risk leukemia group. ETP-ALLs showed increased biosynthesis of phospholipids and sphingolipids and were specifically sensitive to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme in the mevalonate pathway. Mechanistically, inhibition of cholesterol synthesis inhibited oncogenic AKT1 signaling and suppressed MYC expression via loss of chromatin accessibility at a leukemia stem cell–specific long-range MYC enhancer. In all, these results identify the mevalonate pathway as a druggable novel vulnerability in high-risk ETP-ALL cells and uncover an unanticipated critical role for cholesterol biosynthesis in signal transduction and epigenetic circuitries driving leukemia cell growth and survival. Significance: Overtly distinct cell metabolic pathways operate in ETP- and T-ALL pointing to specific metabolic vulnerabilities. Inhibition of mevalonate biosynthesis selectively blocks oncogenic AKT–MYC signaling in ETP-ALL and suppresses leukemia cell growth. Ultimately, these results will inform the development of novel tailored and more effective treatments for patients with high-risk ETP-ALL. This article is highlighted in the In This Issue feature, p. 587

Abstract Central nervous system (CNS) involvement in patients with newly diagnosed acute myeloid leukemia (AML) is rare, and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials for patients with newly diagnosed AML. In all, 3240 patients with AML were analyzed, and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies in which LP was performed at the discretion of the investigator (0.86% vs 1.41%; P = .18). There was no significant difference in the rate of complete remission (CR) among patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs 59.3%-60%). The median overall survival (OS) for patients who were CNS positive, who had other EMD, or who had no EMD was 11.4, 11.3, and 12.7 months, respectively. There was no difference in OS among patients with CNS involvement, those with other EMD (hazard ratio [HR], 0.96; adjusted P = .84), and those with no EMD (HR, 1.19; adjusted P = .44). In conclusion, the reported incidence of CNS involvement in patients with newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis in and of itself does not seem to portend a poor prognosis for achieving an initial CR or for OS.