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: Introduction Patients aged 〉60 years (y) with acute myeloid leukemia (AML) have inferior outcomes compared to those 60y with newly diagnosed AML or high-risk MDS combining pano at doses ranging from 20 mg to 60 mg given orally on days 1, 3, 5, and 8 of induction with daunorubicin (dauno) 60 mg/m2 on days 3-5 and ara-C 100mg/m2 continuously on days 3-10 (p+7+3). Patients were allowed retreatment on p+5+2, with pano on days 1, 3, and 5 at the same doses, if the nadir BM biopsy had residual leukemia. Upon attainment of CR/CRi, patients were offered a second p+7+3 or alternative consolidation including allogeneic stem cell transplantation (alloHCT). Dose-limiting toxicity was defined based on unexpected toxicities from 7+3 induction and a standard 3+3 design was utilized for dose escalation. Peripheral blood mononuclear cells were isolated on days 1-5 and HDAC expression and histone acetylation were evaluated by western blot and quantified by densitometry. Results Overall, 22 patients were treated on the PanDA protocol. Treatment was well-tolerated in all dose-cohorts and the MTD was not reached. We treated 6 patients each at the 60 mg and 50 mg dose in the dose expansion phase due to recurrent grade 1 bradycardia. The median age was 67y-60-69y (13), 70-79y (5), and 〉80y (4). Eleven patients had de novo AML, 7 had AML with myelodysplasia related changes, 2 had 2ary AML from MPD, 1 treatment-associated myeloid neoplasm, and 1 had RAEB-2. Two patients had progressed on hypomethylating agents. Thirteen (62%) had intermediate-risk cytogenetics (cyto). Amongst 8 euploid patients, 2 had FLT3-ITDmut, 1 had FLT3-TKDmut and 2 had NPM1mut as the sole abnormality. Seven (33%) patients had complex/monosomic cyto. There were no patients with favorable cyto. There were no protocol-defined DLTs. The most common grade 2-4 TEAEs were febrile neutropenia (77%), electrolyte abnormalities (64%), diarrhea (55%), rash (55%), LFT abnormalities (32%), nausea (27%) and anorexia (27%). Of note, 36% experienced asymptomatic sinus bradycardia peaking on day 6 following pano, dauno, and 5HT3 inhibitor anti-emetics. Additionally, 9% experienced new onset grade 2 atrial fibrillation. There was no evidence of myocardial dysfunction on echocardiogram following induction. SAEs reported on study were sepsis (9%), typhlitis (5%), DIC (5%), pneumonitis (5%), and bowel perforation due to mucorales (5%). There were 2 deaths (9%) during induction, one related to typhlitis and the other to sepsis. Of 20 evaluable patients, 8 (40%) achieved CR/CRi . One patient received study treatment as consolidation, 3 received intermediate/high-dose ara-C, 1 received a hypomethylating agent, 2 underwent alloHCT and 1 had no further therapy. Median overall survival was 10 mos (ITT) and 16 mos for those who achieved a CR/CRi (p=0.005). Median relapse-free survival was 10 mos, range 3-27 mos (Figure 1). Baseline expression of HDAC class 1, 2, 3 and 6 was evaluated and was not found to be associated with response to p+7+3 arguing against a direct role in p+7+3-induced cytotoxicity. However, global histone acetylation change after pano exposure (days 1-3) was significantly associated with eventual chemo-ablation at nadir (Figure 2). Ongoing studies are evaluating markers of DNA damage response and apoptosis in patients treated with PanDA vs. concurrent 7+3 controls. Conclusions The addition of pano to 7+3 induction for older patients with AML is well-tolerated and results in clinical outcomes that are favorable in our very high-risk population. The recommended dose of pano is 50 mg daily on days 1, 3, 5, and 8 when combined with 7+3 induction in future studies. Importantly, histone acetylation change following exposure to pano but not baseline HDAC expression predicts sensitivity to combined therapy. Disclosures Wieduwilt: Sigma-Tau: Research Funding; Alexion: Honoraria. Off Label Use: Panobinostat is approved for multiple myeloma. This paper reports it's use in patients with acute myeloid leukemia.. Olin:Daiichi-Sankyo: Research Funding. Logan:Pharmacyclics: Consultancy; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy. Damon:Atara: Consultancy; Sunesis: Research Funding; McGraw-Hill: Patents & Royalties: Book Chapter; Sigma-Tau: Research Funding. Boyer:Onyx: Speakers Bureau. Andreadis:genentech: Employment; novartis oncology: Research Funding; cellerant: Research Funding; karyopharm: Research Funding; McGraw-Hill: Patents & Royalties: Book Chapter; Pfizer: Honoraria; Pharmacyclics: Honoraria.

Description: Background: Current management of chemotherapy and radiation-induced neutropenia is unsatisfactory with frequent infection-related deaths. A novel allogeneic human myeloid progenitor cell product, CLT-008, that is culture-derived from G-CSF mobilized HSCs, can be cryopreserved and infused without HLA matching. Cells are intended to engraft transiently and produce mature myeloid effector cells that migrate to tissues and may mitigate the risk of bacterial or fungal infection for weeks, as has been demonstrated in murine models. Methods: To evaluate the safety of CLT-008, a phase 1 dose escalation study was conducted in subjects with AML, MDS or ALL during consolidation (n=18) or with AML or tAML during first or subsequent induction (n=31). Eligible subjects were age 18 or older and treated with a high-dose or standard-dose cytarabine-based regimen. All 18 consolidation subjects and 23 induction subjects received CLT-008. Subjects received CLT-008 on study day 6 (consolidation 106 or 107cells/kg) or on study day 9 (induction 107 or 3x107 cells/kg). G-CSF was given at 5 µg/kg daily from the day of CLT-008 until the ANC was 500/µL. During induction, 8 non-randomly selected controls received G-CSF without CLT-008. Dose limiting toxicities (DLT) were defined as any grade 3-5 infusion reaction, grade 4-5 organ toxicity (not due to the primary malignancy, infection, pre-existing condition, or initiation of new chemotherapy), any Grade III to IV GVHD, or failure of autologous neutrophil recovery at Day 42 not clearly attributable to another cause. All subjects were followed for 49 days and status was assessed at 6 months. Results: Among 41 currently evaluable subjects, 1 experienced a DLT of grade 3 allergic infusion-related reaction which resolved promptly with steroids and antihistamine. There were no other DLTs and no GVHD of any grade. Treatment-emergent adverse events occurring in 3 or more subjects included febrile neutropenia, infection, mucosal inflammation, fatigue, diarrhea, tachycardia and nausea but were not judged related to the product. Among the 23 induction subjects receiving CLT-008 with G-CSF, there was a reduction in mucositis (WHO grade 2 or greater) and in duration of febrile episodes when compared to the 8 control subjects. CLT-008-derived cells were detectable in the peripheral blood for 6 of 23 induction subjects at 2-10% of nucleated cells using STR-PCR; there was no clear effect on ANC from this chimerism. To date, 8 of 23 induction subjects went on to subsequent HSC transplant. Seven engrafted while one died on post-transplant day 10 from an unrelated cause. Conclusions: CLT-008 was safe and well tolerated in this phase 1 study. Only 1 DLT occurred and the pattern of AEs was as expected for this population. Among the induction subjects treated at 3x107 cells/kg, efficacy signals with respect to mucositis and duration of fever were found in the absence of high-level peripheral blood CLT-008 chimerism. These observations suggest that CLT-008-derived myeloid effector cells preferentially migrate to chemotherapy-damaged mucosal tissues where they could function to mitigate infection risk. Further clinical development is planned in a randomized phase 2 study using an enhanced potency iteration of CLT-008, assessment of tissue-level chimerism, and specific ascertainment of outcomes related to infection and chemotherapy sequellae. Figure 1 Figure 1. Disclosures Wieduwilt: Cellerant Therapeutics: Honoraria, Research Funding. Cerny:Cellerant Therapeutics: Honoraria, Research Funding. Akard:Cellerant Therapeutics: Research Funding. Ustun:Cellerant Therapeutics: Honoraria, Research Funding. Ravandi:Cellerant Therapeutics: Research Funding. Rossetti:Cellerant Therapeutics: Research Funding. Hill:Cellerant Therapeutics: Honoraria, Research Funding. Brown:Cellerant Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Kellerman:Cellerant Therapeutics: Employment, Equity Ownership. Van Syoc:Cellerant Therapeutics: Employment, Equity Ownership. Reed:Cellerant Therapeutics: Employment, Equity Ownership. Andreadis:Cellerant Therapeutics: Research Funding.

Description: Introduction: The rapid technological advances in next generation sequencing (NGS) have allowed oncologists to sequence tumorexomesin a clinically meaningful period of time. NGS allows for identification of alterations that may be potentially targetable by already available Food and Drug Administration (FDA) approved drugs, providing a biologic rational for consideration of therapies and/or experimental treatments (clinical trials) that would not have otherwise been contemplated. Here we report our experience using NGS in a cohort of 60 patients with various lymphoid malignancies. Methods: We retrospectively reviewed the medical charts of 60 patients with various lymphoid malignancies who had undergone NGS. Patients were seen at the UCSD Moores Cancer Center (La Jolla, CA) from October 2012 until March 2016. We collected tumor samples from tissue (Table 1) or peripheral blood from 60 patients that were submitted for testing to Foundation Medicine, a clinical laboratory improvement amendments (CLIA)-certified lab. Hybrid capture based NGS (405 gene panel) was performed (http://www.foundationone.com/). The methods used in this assay have been described in detail in a previous report (He, J. et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016. 127:3004-3014.). Results: Sixty patients including 35 men (58%) and 25 women (42%), were identified with lymphoid malignancies (Table 1). A total of 224 alterations were found by NGS in the entire cohort of 60 individuals. Types of alterations identified included substitutions, indels, copy number alterations (CNAs), and gene fusions. Figure 1 demonstrates the 15 most frequent alterations among the cohort: TP53 mutations (10 patients), IGH rearrangements (9 patients), loss of CDKN2A/B (8 patients), and BCL2 mutations (8 patients). The median number of alterations detected per patient was 3 (range, 0 to 14). Shown in Figure 2, 7 patients (12%) had no reportable alterations, 10 patients (17%) had 1 alteration, and 43 (71%) patients had 2 or more alterations. The maximum number of alterations identified was 14, which occurred in two patients (3%), one with chronic lymphocytic leukemia (CLL) and the other with diffuse large B-cell lymphoma (DLBCL). A total of 49 patients (82%) had potentially actionable alterations using FDA approved drugs and/or experimental therapies (clinical trials) while 11 patients (18%) had no theoretically actionable alterations. Only 3 patientshad an alteration for which an approved drug in the disease is available (on-label) while 45 patients (75%) had an alteration for which an approved drug is available in another disease (off-label). Twenty-three patients (38%), 12 patients (20%), and 10 patients (17%) had 1, 2 and³ 3 FDA targetable alterations, respectively. The median number of theoretical FDA actionable alterations was 1. Conclusions:Most patients with lymphoid malignancies will have alterations that are potentially pharmacologically identified by NGS; however, only a minority of patients will have alterations for which an approved drug in the disease is available (on-label). Patients with lymphoid malignancies who have exhausted standard therapy or who are unable to tolerate chemotherapy may be excellent candidates for matched targeted therapies, ideally administered in the context of a clinical trial. Figure 1 The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 1. The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 2 Figure 2. Disclosures Goodman: Pfizer: Other: Fellowship funding. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurzrock:Serono: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Actuate Therapeutics: Research Funding; Sequenom: Research Funding; X Biotech: Research Funding; Genentech: Research Funding; Curematch: Equity Ownership; Novena: Equity Ownership.

Description: Background Despite advances in therapy, relapsed or refractory (RR) non-Hodgkin lymphoma (NHL) remains a major treatment challenge. Preclinical data support the activity of proteasome inhibitors against lymphoma through multiple mechanisms including activation of the endoplasmic reticulum (ER) stress response and reduction in the threshold for apoptosis in response to chemotherapy. Clinically, proteasome inhibiton with bortezomib added to bendamustine yielded promising results in patients (pts) with indolent NHL with limited additional toxicity. Compared to bortezomib, carfilzomib is a more target specific and potent proteasome inhibitor with less neurotoxicity. We embarked on a multicenter, phase 1b dose escalation trial to assess the combination of carfilzomib with bendamustine and rituximab in pts with RR aggressive or indolent NHL. Methods The primary objective of the study is to determine the maximum tolerated dose (MTD) and recommended phase II dose of carfilzomib when combined with bendamustine and rituximab. The secondary objective is to evaluate the preliminary antitumor activity of the combination in select NHL histologies. Correlative studies examine markers of ER stress and apoptosis in response to treatment. Here we report the preliminary results of the dose escalation phase expected to be completed in Fall 2019. We followed a standard 3+3 design with escalation of the carfilzomib dose in 4 dose level cohorts combined with bendamustine dosed at 90 mg/m2 IV on Days 1 and 2 and Rituximab dosed at 375 mg/m2 IV on Day 9 of cycle 1 and Day 1 of subsequent cycles. Initially, carfilzomib was dosed twice a week with dose level 1 at 15 mg/m2 IV on days 1,2,8,9, 15, and 16. Subsequently, we explored weekly dosing schedules with carfilzomib at 36 mg/m2 (dose level 2), 56 mg/m2 (dose level 3), and 70 mg/m2 (dose level 4) on days 9 and 16 with a 20 mg/m2 starting dose on day 2. Dose limiting toxicity (DLT) was defined as Gr4 or specific Gr3 events attributable to the combination. Pts are treated for up to 6 cycles with an interim PET/CT after cycle 3. Results To date, 10 pts have been treated on the dose escalation phase with one patient currently on study treatment. Overall, 5 pts had diffuse large B-cell lymphoma (DLBCL), 3 mantle cell lymphoma (MCL), 1 follicular lymphoma (FL), and 1 marginal zone lymphoma (MZL). Pts received a median of 3 prior lines of therapy. Four pts were treated on dose level 1, 3 on dose level 2, and 3 on dose level 3. Treatment-emergent Grade 2-4 adverse events included thrombocytopenia in 1 pt (Gr 4), neutropenia in 1 pt (Gr 4), febrile neutropenia in 1 pt (Gr 3), culture negative fevers in 1 pt (Gr 3), nausea/vomiting in 2 pts (Gr 2 and 3), other GI toxicities in 1 pt (Gr 2), lower back pain in 1 pt (Gr 2), arthralgias in 1 pt (Gr 2), and cerebrevoascular ischemia in 1 pt (Gr 2). Two pts had treatment related-SAEs (Gr3 culture negative fevers; Gr 3 febrile neutropenia and Gr 3 vomiting) at dose level 2 and 3 respectively. One patient experienced DLT (Gr 3 febrile neutropenia) at dose level 3. There were no treatment related deaths. Of 10 evaluable pts to date, the overall response rate (ORR) is 40% with 3 pts achieving complete remission (one with FL, one with DLBCL and one with MCL) and one pt with MCL achieving a partial remission. The responder with FL had relapsed disease after achieving prior complete remission with rituximab and bendamustine alone. For the 9 pts who completed study treatment, median duration of treatment was 2.4 months, median progression free survival was 1.9 months and median overall survival was 11.6 months. The median duration of response for the 3 responders who completed therapy was 21.8 months. Conclusion Carfilzomib in combination with bendamustine and rituximab is a safe and well-tolerated treatment for pts with RR NHL. The MTD has not been reached and enrollmemt continues, with dose escalation phase anticipated to complete in Fall 2019. Preliminary data indicate that this combination may have efficacy with an acceptable side effect profile in this heavily pre-treated patient population with limited treatment options. Disclosure: This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program with general research support provided by Amgen. Disclosures Tuscano: Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria; Amgen: Honoraria; Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Reata Pharmaceuticals: Equity Ownership. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy.

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: Background: Outcomes for the treatment of AML with conventional induction chemotherapy (eg, 7+3 cytarabine/daunorubicin regimen) are poor for older adults and those with high-risk/secondary AML. CPX-351 (Vyxeos®), a dual-drug liposomal encapsulation of cytarabine and daunorubicin in a synergistic ratio, was approved by the US FDA in 2017 for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes and is currently under review by the EMA. A large randomized, open-label, multicenter, phase 3 study (ClinicalTrials.gov #NCT01696084) evaluated the efficacy and safety of CPX-351 versus conventional 7+3 chemotherapy in adults aged 60-75 y with newly diagnosed, high-risk/secondary AML (Lancet JE, et al. J Clin Oncol. 2018). In this study, CPX-351 significantly improved median overall survival (OS; primary endpoint) versus 7+3 (9.56 vs 5.95 mo; HR = 0.69 [95% CI: 0.52-0.90]; 1-sided P = 0.003), as well as event-free survival (EFS; 2.53 vs 1.31 mo; HR = 0.74 [95% CI: 0.58-0.96]; 2-sided P = 0.021). CPX-351 was also associated with higher rates of complete remission (CR; 37.3% vs 25.6%; 2-sided P = 0.040) and CR or CR with incomplete platelet or neutrophil recovery (CR+CRi; 47.7% vs 33.3%; 2-sided P = 0.016) versus 7+3, which likely contributed to the higher rate of patients undergoing hematopoietic cell transplantation (HCT) with CPX-351 (34.0% vs 25.0%; 2-sided P = 0.098). HCT is a potentially curative therapy, and the higher rate of HCT observed in the CPX-351 arm could therefore have an impact on long-term survival outcomes. To better understand the contribution of HCT and treatment with CPX-351 versus 7+3 to survival, exploratory analyses using a time-dependent proportional hazards model were performed to evaluate survival in patients who underwent HCT and assess the impact of treatment with CPX-351 versus 7+3 on survival independent of HCT status. Methods: Patients were randomized 1:1 to receive up to 2 induction cycles with CPX-351 (100 units/m2 [cytarabine 100 mg/m2 + daunorubicin 44 mg/m2] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (cytarabine 100 mg/m2/d continuously for 7 d [2nd induction: 5 d] + daunorubicin 60 mg/m2 on Days 1-3 [2nd induction: Days 1-2]). Patients achieving CR or CRi could receive up to 2 consolidations with CPX-351 (65 units/m2 [cytarabine 65 mg/m2 + daunorubicin 29 mg/m2] on Days 1 and 3) or 5+2 (as in 2nd induction). Patients could receive HCT at the discretion of the treating physician. Results: A total of 309 patients were enrolled in the study (CPX-351: n = 153; 7+3: n = 156), and baseline characteristics were balanced between arms. A total of 52 (34.0%) patients in the CPX-351 arm and 39 (25.0%) in the 7+3 arm underwent HCT; most were 60-69 y of age (CPX-351: 69.2%; 7+3: 84.6%), had ECOG performance status ≤1 (CPX-351: 92.3%; 7+3: 94.9%), and were in CR (CPX-351: 57.7%; 7+3: 48.7%) or CRi (CPX-351: 19.2%; 7+3: 12.8%). Median time to HCT from first study dose was similar with CPX-351 (114.5 d) and 7+3 (113.0 d). Similar to the primary endpoint analysis, median OS landmarked from the time of HCT was significantly improved with CPX-351 versus 7+3 (not reached vs 10.25 mo; HR = 0.46 [95% CI: 0.24-0.89]). Further, in the current exploratory analyses in which HCT was treated as a time-dependent covariate, the HRs remained strongly in favor of CPX-351 versus 7+3 for OS (HR = 0.71) and EFS (HR = 0.74), with the upper bounds of the 95% CIs below 1.0 (Table). These results suggest CPX-351 may be associated with prolonged OS and EFS that is independent of HCT. The adverse event profile of CPX-351 was generally consistent with the known safety profile of conventional 7+3. Grade 3-5 adverse events reported in ≥10% of patients in the CPX-351 or 7+3 cohorts included febrile neutropenia (68.0% vs 70.9%), pneumonia (19.6% vs 14.6%), and hypoxia (13.1% vs 15.2%). Early mortality rates with CPX-351 and 7+3, respectively, were 5.9% and 10.6% at Day 30 and 13.7% and 21.2% at Day 60. Conclusions: Treatment with CPX-351 was associated with significantly longer median OS and EFS, as well as a higher proportion of patients achieving remission and undergoing HCT, compared with conventional 7+3 chemotherapy in this population of older patients with newly diagnosed, high-risk/secondary AML. Further, while it is expected that HCT had a positive impact on survival in this study, exploratory analyses suggest that CPX-351 produced positive OS and EFS outcomes independent of HCT. Disclosures Lin: Jazz Pharmaceuticals: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Arog: Research Funding. Ritchie:NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding. Stuart:Sunesis Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Agios: Research Funding; Astellas: Research Funding; Bayer AG: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Strickland:Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxalta: 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, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding. Bixby:GlycoMimetics: Research Funding. Kolitz:Magellan Health: Consultancy, Honoraria. Schiller:bluebird bio: Research Funding; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wieduwilt:Leadiant: Research Funding; Reata Pharmaceuticals: Equity Ownership; Merck: Research Funding; Shire: Research Funding; Amgen: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Ryan:University of Rochester: Patents & Royalties; AbbVie: Equity Ownership. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Chiarella:Celator/Jazz Pharmaceuticals: Employment, Equity Ownership. Louie:Jazz Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties. Uy:GlycoMimetics: Consultancy; Curis: Consultancy.

Description: Introduction: Patients (pts) with newly diagnosed, secondary AML (sAML) may have previously received hypomethylating agent (HMA) therapy for an antecedent hematologic malignancy (eg, myelodysplastic syndrome [MDS]). Outcomes for pts with MDS who progress following HMA therapy are typically poor, with remission rates

Description: Clinical and preclinical findings suggest that PD-L1 overexpression on lymphoblasts and in the bone marrow microenvironment may mediate resistance to blinatumomab by inhibiting T-cell activation. We report preliminary findings from an ongoing phase I/II multicenter trial to evaluate the safety and efficacy of blinatumomab with pembrolizumab in adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and a high bone marrow lymphoblast percentage (NCT 03160079). The primary objective of this Phase I/II trial is to determine overall response rate (ORR = complete response (CR) + complete response with partial hematologic recovery (CRh) rate) after 1-2 cycles of blinatumomab with pembrolizumab, with key secondary endpoints of adverse events (AEs), minimal residual disease (MRD)-negative CR/CRh rate, 2-year disease-free and overall survival, and allogeneic HCT rate. Eligible patients are 18 years of age or older with R/R B-ALL after ≥ 1 prior line of therapy (including Philadelphia chromosome positive (Ph+) B-ALL failing one second or third generation tyrosine kinase inhibitor) and 〉50% lymphoblasts on screening bone marrow sample. Patients receive blinatumomab by continuous IV at 9 mcg/day on days 1-7 and 28 mcg/day on days 8-28 of cycle 1, then 28 mcg/day on days 1-28 in subsequent cycles. Pembrolizumab 200 mg IV is given on days 15 and 36 of each 42-day cycle. Patients in CR/CRh after 1-2 cycles complete a maximum of 5 cycles. A safety cohort of up to 6 patients assessed safety by 3+3 design. Dose-limiting toxicities (DLTs) were defined as Grade 3 or 4 non-hematologic AEs related to the addition of pembrolizumab to blinatumomab with a DLT monitoring period of 28 days from the first pembrolizumab dose. At the time of this analysis, 5 patients have been enrolled and treated with all 5 completing the DLT monitoring period. Patients had a median age of 60 years (range 22-74) and one had Ph+ disease. Median bone marrow lymphoblast percentage at time of enrollment was 84% (range 53-90). Patients received a median of 1 cycle (range 1-3) of blinatumomab with pembrolizumab. Common AEs included fever, headache, increased bilirubin, nausea, neurotoxicity, and tachycardia. Grade 3-4 non-hematologic AEs included disseminated intravascular coagulation, hyperferritinemia, hypokalemia, subdural hematoma, encephalopathy, hyponatremia, and macrophage activation syndrome in 1 patient (all related to blinatumomab), hyperbilirubinemia and elevated AST in 1 patient, and hypertriglyceridemia in 1 patient. No grade 3 or greater immune-related AEs have occurred. No pembrolizumab-related DLTs occurred in the first 5 patients in the safety cohort and enrollment is now proceeding in the dose-expansion cohort. The ORR was 50% with 2/4 evaluable patients achieving a CR. One patient achieved an MRD-negative CR in cycle 1 and completed 3 cycles before proceeding to allogeneic HCT. One patient discontinued treatment due to subdural hemorrhage and macrophage activation syndrome during cycle 1 and achieved a CR. Both patients remain in CR for over 6 months. Two patients discontinued treatment due to refractory or progressive disease. The one patient not evaluable for response withdrew from study therapy after 1 cycle without ALL progression. Patient, disease, and treatment characteristics as well as outcomes are summarized in the Table. Blinatumomab with pembrolizumab is safe for adults with R/R B-ALL and a high bone marrow lymphoblast percentage. Enrollment continues in the dose-expansion cohort to assess efficacy. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Costello:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding; Takeda: Honoraria, Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Wieduwilt:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Pembrolizumab (given off label)to enhance the efficacy of blinatumomab (given on label) for relaped/refractory B-cell acute lymphoblastic leukemia

Description: Optimal post-remission therapy for adolescents and young adults (AYAs, 16-39 years) with Ph-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not well established. We hypothesized that post-remission therapy with a pediatric-inspired regimen would yield superior outcomes to myeloablative allogeneic HCT for AYA patients with Ph- ALL in CR1. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a contemporary matched AYA cohort undergoing myeloablative allogeneic HCT in CR1 reported to the CIBMTR (Table). The allogeneic HCT cohort consisted of patients 16-39 years of age with Ph- ALL in CR1 undergoing myeloablative transplant from a matched sibling/relative or unrelated donor using peripheral blood or bone marrow stem cells between 11/2002 and 8/2012 in the United States. Patients receiving post-remission therapy with pediatric-inspired chemotherapy had superior OS (P