ALBERT

Description: Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after

Description: Background: Flotetuzumab (FLZ; MGD006/S80880) is a novel CD123 x CD3 bispecific DART® protein being tested in a Phase 1/2 study (NCT02152956) in patients with relapsed/refractory acute myeloid leukemia (AML). As with all T-cell redirecting therapies, cytokine secretion, inherent in T-cell activation, with ensuing potential for cytokine release syndrome (CRS), remains an important side effect. We have previously reported that multi-step dosing mitigates CRS severity (1). CRS diagnosis and treatment is guided by the occurrence of non-specific clinical signs, such as fever, chills, hypotension and tachycardia. Therefore, identification of predictors of CRS will be useful for optimal pt. management. Here we report on potential biomarkers of CRS severity that may help guide CRS management. Methods: Data from pts treated with FLZ at RP2D (lead-in dose of 30ng/kg/d for 3d, 100ng/kg/d for 4d for week 1 followed by 500ng/kg/d CIV week 2-4 of cycle 1, and a 4d-on/3d-off schedule for Cycle 2 and beyond in 28-day cycles) was collected and analyzed. Incidence and severity of CRS were analyzed for correlation with cytokine levels and changes in BM blasts. Relation between immune cells (T-cell subsets, monocytes) with tumor burden, percent CD123+ AML blasts, and CD123 expression, were interrogated as potential determinants of CRS. Administration, dose and frequency of tocilizumab (TCZ), an IL-6 receptor antagonist, were evaluated for their relationship with CRS severity, frequency, CRP and cytokine levels. Results: 30 pts were dosed at RP2D. Most pts experienced mild to moderate CRS (G1 26.7%, G2 60%) of short duration (median 1 day(d), range 1-26 d) and were conservatively managed to full resolution. Grade ≥ 3 events occurred in 4/30 pts (13%), with vasopressors use in 2 pts, and a median duration of 2.5 d (range 2-13 d). CRS frequency decreased with time on treatment: 42% occurred within the first week (LID), 39.6% occurring in week 2 (step up to 500ng/kg/day) and 18% occurring during week 3 and 4. IL-6 levels showed the best relationship with CRS severity, as previously shown (1). IL-6 levels, however, did not correlate with response. Twenty pts (67%) received at least one dose of TCZ (median 2 doses/pt; range 1-12 doses). As anticipated, mean IL-6 levels increased after administration of TCZ. CRS severity showed a relationship with the baseline frequency of circulating CD4+ cells (median 47% in G1 vs 73% in G ≥2, p = 0.0082), while CD8+ cell frequency did not correlate with CRS. Disease burden (absolute AML blasts, % CD123 AML blasts), CD123 expression on AML blasts, monocytes levels or effector-to-target ratio in the peripheral blood did not show a relationship with CRS severity. Importantly, CRS severity was not correlated with FLZ anti-leukemic activity. Conclusion: The frequency of CD4+ cells at baseline may be a potential biomarker for identifying pts at risk of more severe CRS. Early use of TCZ can effectively modify the activity of IL-6, a significant contributor to CRS, and blunt CRS severity. Since severity of CRS and IL-6 levels did not correlate with FLZ anti-leukemic activity, blunting its severity should be aggressively pursued. Early identification of pts at greater CRS risk together with multistep dosing (1) and early use of TCZ can effectively manage CRS with no impact on FLZ anti-leukemic activity.Jacobs et al. ASH 2017, abstract #3856 Disclosures Jacobs: MacroGenics: Employment. Viero:Servier: Employment. Baughman:MacroGenics: Employment. Sun:MacroGenics: Employment. Ying:Macrogenics: Employment. Muth:MacroGenics: Employment. Hong:MacroGenics: Employment. Sweet:BMS: Honoraria; Agios: Consultancy; Phizer: Consultancy; Astellas: Consultancy; Jazz: Speakers Bureau; Jazz: Speakers Bureau; BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Agios: Consultancy; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau. Uy:Curis: Consultancy; GlycoMimetics: Consultancy. Ravandi:Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria. Foster:Celgene: Research Funding; Macrogenics: Research Funding; Pfizer: Research Funding; Shire: Honoraria. Rizzieri:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arellano:Cephalon: Research Funding. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Topp:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Lelièvre:Servier: Employment. Lowenberg:Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; international Scientific Advisory Board, Institute Gustave Roussy, Paris: Membership on an entity's Board of Directors or advisory committees; "Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands): Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Editorial Board "International Journal of Hematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board "The Netherlands Journal of Medicine": Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees. Wigginton:MacroGenics: Employment. Davidson-Moncada:MacroGenics: Employment.

Description: BACKGROUND: Allogenic hematopoietic stem cell transplant (SCT) is a potentially curative option for patients with acute myeloid leukemia (AML). However, patients who are older, are ineligible for intensive chemotherapy due to significant comorbidities, or have biologically aggressive and refractory disease are not often considered as viable SCT candidates. Venetoclax, a highly selective, potent BCL-2 inhibitor that induces apoptosis in AML cells, has resulted in high rates of durable remission when combined with hypomethylating agents (HMAs) or low dose cytarabine (LDAC), in older patients traditionally considered high risk and ineligible for standard induction chemotherapy. Here, patients who received SCT after venetoclax-based treatments were analyzed to determine the impact of SCT on patient outcomes. METHODS: This study includes patients from the global, open-label phase 1b (NCT02203773) and phase 1/2 (NCT02287233) clinical trials studying the safety and efficacy of venetoclax in combination with the HMAs decitabine or azacitidine, and LDAC, respectively. Patients had newly diagnosed AML and were ineligible for intensive chemotherapy due to comorbidities or age. Patients in the venetoclax plus HMA trial (n=212) were treated with venetoclax (400, 800, or 1200 mg) coadministered with either 20 mg/m2 of intravenous decitabine on days 1-5 or 75 mg/m2 of intravenous or subcutaneous azacitidine on days 1-7 within each 28-day cycle. Patients in the venetoclax plus LDAC trial (n=92) were treated with venetoclax (600 or 800 mg), and with LDAC (20 mg/m2 daily) subcutaneously administered on days 1-10 of each cycle. Patients proceeding to SCT were evaluated for efficacy endpoints including best response (complete remission [CR] or CR with partial hematologic recovery [CRh]), time to best response, time from last dose of venetoclax until SCT, and 12-month post-SCT survival. RESULTS: Of 304 patients treated with venetoclax-based therapy, 31 (10%) proceeded to have allogenic SCT, all of whom were treated in the US. Key demographics for those who received SCT are shown in the Table. The median age was 69 (range: 63-76), 29% had secondary AML, and 39% had adverse cytogenetic risk. The median time on study drug was 3.7 months (range: 0.9-20), and the median time from last dose of venetoclax to SCT was 1.2 months (range: 0.4-10). Twenty-two (71%) patients achieved CR or CRh, with a median time to best response of 2.3 months (range: 0.9-7.1). The median survival time for those that achieved CR (n=16) and CRh (n=6) was 28 months (range: 5.6-54) and 32 months (range: 14-41), respectively. Of 22 patients that achieved CR or CRh, 13 (59%) remained in remission for at least 12 months posttransplant. Across all patients, 55% (17/31) remained in remission for at least one year after SCT, with 12 such patients having remained in remission for ≥2 years. Overall, 68% (21/31) of patients remained alive at 12 months posttransplant. CONCLUSIONS: Venetoclax in combination with either HMAs or LDAC has led to high rates of early, deep and durable responses in untreated AML patients ineligible for standard induction chemotherapy. In this combined study of over 300 such patients, 10% went on to receive stem cell transplant, a majority of whom remained alive and in remission for at least 12 months thereafter. Nearly 40% of SCT patients had durable remissions (≥2 years), suggesting that venetoclax-based regimens prior to SCT, even in patients deemed unfit for standard induction chemotherapy, may provide a path to curative therapy. Disclosures Pratz: Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium/Takeda: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria. Arellano:Gilead: Consultancy. Letai:Zeno Pharmaceuticals, Vivid Bioscience, Flash Therapeutics, Dialectic Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder or Advisory Board member; AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding. Thirman:Merck: Research Funding; Roche/Genentech: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; Up to Date: Honoraria; AbbVie: Consultancy, Research Funding; Astra Zeneca: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Janssen: Consultancy. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: 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; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: 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; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Becker:The France Foundation: Honoraria; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; Accordant Health Services/Caremark: Consultancy. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Jiang:AbbVie, Inc.: Employment, Other: stock or options. Hayslip:AbbVie, Inc.: Employment, Other: stock or options. Potluri:AbbVie, Inc.: Employment, Other: Stock/stock options. Pollyea:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Diachii Sankyo: 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.

Description: Acute myeloid leukemia (AML) blasts and leukemia stem cells highly express the α chain of the IL-3 receptor (CD123), compared to normal hematopoietic stem cells. CD123 expression is associated with high-risk features, increased risk of induction failure and poor prognosis (Vergez F, et al. Haematologica 2011; 96: 1792-8). Flotetuzumab (FLZ), a CD123 × CD3 bispecific DART molecule, is being tested in a phase 1/2 study in patients with relapsed/refractory (R/R) AML. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day (d) administered as a 7-day/week continuous infusion. Patients receive a lead-in dose (30 ng/kg/d x 3d then 100 ng/kg/d x 4d) during week (W) 1, followed by 500 ng/kg/d during W2-4 of cycle 1, and a 4d on/3 d off schedule for cycle 2 and beyond. Disease status was assessed by modified IWG criteria; samples were collected to investigate candidate biomarkers, including CD123 receptor density/cell (RD), and gene expression profiling using the NanoString® PanCancer IO 360™ assay. This platform was used to assess the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures in bone marrow (BM) samples from patients treated with FLZ. Thirty patients with R/R AML, median age 64.5 years, received FLZ at the RP2D. Most patients enrolled had primary refractory disease (60% [18/30; 14 to cytotoxic chemotherapy (refractory to ≥ 2 induction attempts, or first CR with initial CR

Description: Background: Although approximately half of adult patients with acute lymphoblastic leukemia (ALL) achieve long-term survival, those who relapse have poor long-term outcomes (El Fakih et al. Hematol Oncol Stem Cell Ther. 2017; Oriol et al. Haematologica. 2010). The initial report of Phase 1 of ZUMA-3, the Phase 1/2 trial of KTE-C19 for treatment of relapsed/refractory (R/R) ALL (NCT02614066), has thus far demonstrated promising efficacy among patients infused with KTE-C19, with a 71% complete remission (CR) rate (CR or CR with incomplete hematologic recovery [CRi]), 88% undetectable minimal residual disease (MRD), and manageable toxicity across all doses (Shah et al. ASH 2017. #888). Here, we present updated safety and efficacy data from Phase 1 of ZUMA-3. Methods: Adult patients (≥ 18 y) with R/R ALL (Ph+ allowed), 〉 5% bone marrow blasts, and ECOG 0-1 received 2, 1, or 0.5 × 106 CAR T cells/kg after low-dose conditioning chemotherapy with fludarabine 25 mg/m2/day for 3 days and a single dose of cyclophosphamide 900 mg/m2 on the third day of conditioning. The primary endpoint for Phase 1 was incidence of dose-limiting toxicities (DLTs). Key secondary endpoints included incidence and time to onset and resolution of adverse events (AEs), rate of undetectable MRD remission in the bone marrow using flow cytometry, and duration of remission. KTE-C19 expansion and persistence were also assessed. Safety analyses included all patients who received KTE-C19, and patients with ≥ 2 months of follow-up were evaluated for efficacy. Results: As of April 12, 2018, 35 patients have received KTE-C19 with a median follow-up of 11 months (range, 2 - 25 months). The median age was 40 years (range, 18 - 69 years), 51% of patients were male, 66% had ECOG 1, 13 patients (37%) had prior blinatumomab, and 60% had received ≥ 3 prior lines of treatment. The median bone marrow blast burden at screening was 70% (range, 5 - 100). Six patients received the 2 × 106 cells/kg dose, 14 received 1 × 106 cells/kg, and 15 received 0.5 × 106 cells/kg. No DLTs were observed in the DLT period. The most common Grade ≥ 3 AEs were hypotension (40%), pyrexia (34%), decreased platelet counts (34%), and anemia (31%). Grade ≥ 3 CRS occurred in 9 patients (26%), with a median time to onset of 5 days (range, 1 - 15 days). There were 2 KTE-C19-related Grade 5 events: 1 cerebral infarction at the 0.5 × 106 cells/kg dose and 1 previously reported multiorgan failure secondary to cytokine release syndrome (CRS) at the 2 × 106 cells/kg dose. Grade ≥ 3 CRS resolved in all patients (not including 2 patients with a Grade 5 event), and the median time to resolution was 11 days (range, 7 - 42 days). Grade ≥ 3 treatment-emergent neurologic events occurred in 16 patients (46%), and the median time to onset was 7 days (range, 4 - 24 days). With the exception of 2 patients with unresolved neurologic events due to death, Grade ≥ 3 neurologic events resolved in all patients (14/14), with a median time to resolution of 17 days (range, 6 - 53 days). Among the 32 patients evaluable for response, the overall rate of undetectable MRD was 78% (95% CI, 60% - 91%). CR or CRi was achieved by 23 patients (72%), and 1 patient (3%) had blast-free BM. KTE-C19 levels were examined in 23 patients as of July 31, 2017. Robust KTE-C19 expansion was observed across all dose levels assessed. Conclusion: High rates of remission were achieved by adult patients with R/R ALL, with approximately three-quarters of patients achieving CR or CRi with undetectable MRD after a single dose of KTE-C19 in ZUMA-3. The safety profile was generally manageable, and most cases of high-grade CRS and neurologic events resolved. These results demonstrate that KTE-C19 offers clinical benefit for patients with otherwise limited treatment options. Disclosures Wierda: AbbVie, Inc: Research Funding; Genentech: Research Funding. Bishop:United Healthcare: Employment; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Speakers Bureau; Juneau Therapeutics: Speakers Bureau; Novartis Pharmaceuticals Corporation: Speakers Bureau. Logan:Adaptive Biotech: Consultancy; Napajen: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy; Astellas: Research Funding; Pharmacyclics: Research Funding; Kite: Research Funding. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Holmes:Unum: Research Funding; Seattle Genetics: Research Funding, Speakers Bureau; Novartis: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Rigel: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy. Abedi:Seattle Genetics: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Research Funding; CIRM: Research Funding; BMS: Speakers Bureau; Takeda: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding. Arellano:Cephalon: Research Funding. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy. Mardiros:Kite, a Gilead Company: Employment; Kite, a Gilead Company: Equity Ownership; Mustang Bio: Patents & Royalties; Kite, a Gilead Company: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Shen:Zhejiang DTRM Biopharma LLC: Other: Clinical Operations Director. Vezan:Kite Pharma: Employment; Kite, Gilead, Abbv, MRK: Equity Ownership. Jain:Kite Pharma, Amgen: Equity Ownership; Kite Pharma: Employment; Kite Pharma: Patents & Royalties.

Description: Background: Cytokine release syndrome (CRS) management in acute myeloid leukemia (AML) patients treated with flotetuzumab, an investigational CD123xCD3 bispecific DART® molecule for T cell redirected therapy. CRS is a hallmark of T cell activating therapy and can be correlated with efficacy, specifically, with CAR-T cells(1). Identification of patients at risk for high grade CRS will help guide CRS management. Flotetuzumab (MGD006) is anovel CD123xCD3 bispecific DART® molecule in Phase 1/2 testing in patients with relapsed/ refractory AML. Several strategies have been successfully employed to mitigate CRS severity, some have been previously reported (2, 3). Here we report on further refinement of CRS management and subsequent investigation of potentiel predictive biomarkers of severity. Methods: The recommended phase 2 dose (RP2D) of flotetuzumab is 500ng/kg/d CIV. Week 1 comprises a step-wise lead-in dose (LID) (1-step: 100 ng/kg/day days 1-4; 2-step: 30ng/kg/d for 3days, 100ng/kg/d for 4days, or multi-step (MS) LID at 30, 60, 100, 200, 300, 400 and 500 ng/kg/day each for 24 hours) in order to improve flotetuzumab tolerability. Tocilizumab usage recommended early in CRS management. The relationships between immune cells (T-cell subsets, monocytes) and tumor burden (percent CD123+ AML blasts, CD123 expression) were further interrogated as potential determinants of CRS. Results: 50 patients have been treated at the RP2D. While almost all patients experienced IRR/CRS events, the majority of these patients experienced IRR/CRS that were mild-moderate in severity (28% Grade(G)1, 62% G2, and 8% G3), of short duration (median 1 day for G1, 2 days G2, 2.5 days G3), and resolved completely with no clinical sequalae reported. Most CRS events occured in the first week of treatment (38.3%) and gradually decreased with continuous dosing (24.8%, 7.4%, and 4.3% during weeks 2-4, respectively). Several key interventions have helped mitigate CRS severity. Sequential increment in steps of LID schedules (1 step, 2-step or multi-step LID) have successfully decreased CRS severity and incidence. For example, CRS mean grade±SEM for week 1 was 2.0±0.26 vs 1.4±0.72 vs 1.5±0.63 and for week 4, 0.67±0.42 vs 0.2 ±0.50 vs 0.1 ±0.50 (1 step, 2-step or multi-step LID, respectively). Moreover, LID improved overall tolerability. Introduction of early use of tocilizumab has helped forestall CRS development; 27 patients received tocilizumab (10 doses for G1, 27 for G2, and 2 for G3 events), only 5 pts have required steroids (4 for G2 and 1 for G3), and no pts have required vasopressor support. Blunting of CRS events did not impact antileukemic activity. CRS severity showed a relationship with baseline frequency of circulating CD4+ cells (mean 0.2 K/µL in patients with no CRS vs. 1.0 K/µL in G1 vs 1.6 K/µL in G ≥2, p 〈 0.000.1), and peak CRS grade in week 1. Conclusion: Like other T-cell activating therapies, flotetuzumab is associated with CRS. Several mitigating factors have helped to blunt the severity of CRS, including lead-in dosing and early tocilizumab usage. Circulating CD4+ cells at baseline continues to be associated with CRS risk, and may be a helpful marker to identify patients at increased risk for CRS. 1. Maude, SL. et al. Managing Cytokine Release Syndrome Associated With Novel T Cell-Engaging Therapies. Cancer J. 2014; 20(2): 119-122. 2. Jacobs, K, et al.Lead-in Dose Optimization to Mitigate Cytokine Release Syndrome in AML and MDS Patients Treated with Flotetuzumab, a CD123 x CD3 Dart® Molecule for T-Cell Redirected Therapy. Blood 2017 130:3856. 3. Jacobs, K, et al.Management of Cytokine Release Syndrome in AML Patients Treated with Flotetuzumab, a CD123 x CD3 Bispecific Dart® Molecule for T-Cell Redirected Therapy. Blood 2018 132:2738. Disclosures Bakkacha: Macrogenics,Inc: Employment, Equity Ownership. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Agios: Consultancy, Honoraria. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celyad: Membership on an entity's Board of Directors or advisory committees. Sweet:Pfizer: Consultancy; Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Consultancy; Jazz: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Emadi:Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wieduwilt:Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Ravandi:Cyclacel LTD: Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding. Tran:MacroGenics: Employment. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Baughman:MacroGenics, Inc.: Employment, Equity Ownership. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:macrogenics: Employment, Equity Ownership; western oncolytics: Consultancy, Other: consultancy. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Walter:Daiichi Sankyo: Consultancy; Amgen: Consultancy; Agios: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy. Davidson:Macrogenics,Inc: Employment, Equity Ownership. DiPersio:Incyte: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm Therapeutics: Consultancy; Bioline Rx: Research Funding, Speakers Bureau; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau. Jacobs:Macrogenics,Inc: Employment, Equity Ownership.

Description: Introduction: Previous studies have suggested a greater graft versus leukemia (GvL) effect among patients (pts.) with chronic myeloid leukemia (CML) who received hamatopoietic progenitor cell transplants (HPCT) from volunteer unrelated donors (VUD) compared with CML pts. who received matched related donor (MRD) transplants. We analyzed the incidence of relapse and survival among pts. with acute leukemia (AL) to determine whether graft source (VUD vs. MRD) had an impact on relapse or survival after allogeneic HPCT. Methods: We analyzed 308 pts. with AML (N=228) and ALL (N=80) who received BM or blood HPCT from MRD (N= 224) or VUD (N= 84). The primary goal was to determine the incidence of post-transplant relapse and factors associated with relapsed disease. The secondary endpoint was survival. Relapsed disease was defined as presence of active leukemia (by morphologic, flow cytometric, cytogenetic, or molecular testing) at the time of transplant. Kaplan-Meier estimates of relapse and survival were calculated, and log rank statistics were used to compare the survival curves. 2-tailed t-tests were used to compare characteristics among relapsed pts. Significant variables on univariate analysis were entered into a Cox regression model for multivariable analysis. A p-value ≤ 0.05 was deemed significant. IRB approval was obtained for this retrospective study. Results: 72/228 (32%) pts. with AML and 27/80 (34%) pts. with ALL relapsed at a median of 135 days post-transplant. Relapse was significantly higher among pts. with active leukemia at the time of transplant (44/99, 44%) and in recipients of grafts from MRD (82/224, 37%), compared with patients in remission (55/209, 26%) at time of transplant and recipients of VUD grafts (17/84, 20%) (p= 0.008 and 0.003 respectively). Stratifying for disease status at transplant, the graft source was significantly associated with the incidence of relapse only in the subset of 99 pts. with active disease at transplant, with 78% relapse among pts. with active AL who received MRD transplants compared with 42% relapse among pts. with active AL transplanted with grafts from VUD (P=0.03) (fig. 1). However, there was no significant difference in overall post-transplant survival among recipients of MRD and VUD (P=0.82). Fig. 1. Fig. 1. Relapsed and non-relapsed pts. had similar age, graft type (PBSC vs. BMT), conditioning regimen, and GVHD prophylaxis (data not shown). Conclusions: Overall outcome for pts. with AL who receive allogeneic transplants with active disease at the time of transplant is poor. While pts. with active AL transplanted with grafts from VUD have less post-transplant relapse than those transplanted with grafts from MRD, overall survival was similar due to greater non-relapse mortality. While this retrospective study could not account for other significant factors that may affect relapse, such as the longer interval from diagnosis to transplant for recipients of VUD grafts, these results indicate that decreasing treatment-related mortality may accentuate the benefit of the enhanced GvL effect of VUD transplant.