NonAmgen Sponsored Studies EHA 2020 Abstract Number Type

Non-Amgen Sponsored Studies – EHA 2020 Abstract Number Type of presentation Title EP 401 Blinatumomab Use During Consolidation in Adult Patients With High-risk, Philadelphia Poster Chromosome-negative Acute Lymphoblastic leukemia: Preliminary Results of the BLIN 01 Trial EP 414 Dose Reduced Chemotherapy in Combination with Blinatumomab for Newly Diagnosed Older Patients with Ph-negative B-precursor ALL: First Results of the BOLD TRIAL Poster EP 392 Tumor Burden and Outcome after Blinatumomab in Adult B-cell Acute Lymphoblastic Leukemia. Results of the French-cyto Study Poster Table of content: Amgen Sponsored Studies 1 Do not copy or distribute. © 2020 Amgen. All rights reserved

BLINATUMOMAB USE DURING CONSOLIDATION IN ADULT PATIENTS WITH HIGHRISK, PHILADELPHIA CHROMOSOME-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA: PRELIMINARY RESULTS OF THE BLIN 01 TRIAL JM Ribera, S Mercadal, P Barba, P Montesinos, MJ Moreno, J Esteve, R Martino, P Martfnez, ML Amigo, N Alonso, J Gonzalez-Campos, T Bernal, JM Hernandez-Rivas, J Ciudad, S Barrena, A, Orfao, on Behalf of the PETHEMA Group, Spanish Society of Hematology 2 Do not copy or distribute. © 2020 Amgen. All rights reserved

Background and Objective § Background. Based on the results of the BLAST trial, blinatumomab was approved for use in patients with measurable residual disease (MRD)-positive, Philadelphia chromosome-negative (Ph-neg) acute lymphoblastic leukemia (ALL) in either first or subsequent complete remission (CR). However, its use as consolidation in first CR patients with low-level MRD has not been studied. § Aim. To report the preliminary results (focused on feasibility and effectiveness) of the Phase II BLIN 01 trial (Clinical. Trials. gov Identifier: NCT 03523429), in which two blinatumomab cycles were given instead of 2 out of the 6 consolidation cycles in adult patients with high-risk (HR) Ph-neg B-cell precursor (BCP) ALL (HR BCP-ALL) with MRD levels <0. 1% after induction therapy. 4 Do not copy or distribute. © 2020 Amgen. All rights reserved

Patients and Methods § HR BCP-ALL definition. Any ALL in patients over 18 years-old with one of the following characteristics: age>35 years, WBC count>30 x 109/ L, pro-B phenotype, t(4; 11)/KTMT 2 A or MLL rearrangements or complex karyotype. § Treatment. PETHEMA HR 11 trial (JM Ribera at al. Blood 2019; 134 [Supplement 1]: 826). Patients in CR after the first induction cycle and MRD <0. 1% entered into the trial and received 6 consolidation cycles: cycles 1, 2, 4 and 5 included chemotherapy with HD-MTX, HD ARAC and ASP and cycles 3 and 6 included blinatumomab (28 µg/day CIV infusion over 4 weeks). § Main objective. Reduction of the MRD levels after cycles 3 and 6. Feasibility of blinatumomab between HD chemotherapy cycles, DFS and OS, and parallel comparison with a similar group of patients treated according to the PETHEMA HR 11 trial not receiving blinatumomab. § Sample size: 38 patients. ALL: acute lymphoblastic leukaemia; Asp: Aspartic acid; BCP: B-cell precursor; CIV: continuous intravenous; CR: complete remission; DFS: disease free survival; HD ARAC: High-dose cytarabine; HD-MTX: high-dose methotrexate; HR: high rate; MRD: measurable residual disease; OS: overall survival; WBC: white blood cell 5 Do not copy or distribute. © 2020 Amgen. All rights reserved

Results(1/2) Patients accrual (January 2020), ALL-HR-11 § 14 patients screened, 11 (6 M/ 5 F) valid. Median age (range) 39 (31 -56) yrs. EGIL phenotype: common (n=10), pre-B (n=1). Induction 1 § Median MRD level § Inclusion : 0. 03% (range: <0. 0002%-0. 09%), § End of cycle 3: 0. 001% (0. 0002%-0. 001%) § End of cycle 6: <0. 0002% (range: <0. 0002%0. 003%). § Follow-up (median 18 months [ 5 -23]) only one patient has relapsed and all patients are alive. 6 Morphologic CR Centralized MRD <0. 1% Study entry Early Consolidation 1 + 2 + Blinatumomab Centralized MRD <0. 01% Delayed consolidation 1+ 2+Blinatumomab Maintenance End of therapy Follow-up (5 -yr) ALL: acute lymphoblastic leukemia; CR: complete remission; EGIL: European Group for the Immunological Classification of Leukaemias; MRD: measurable residual disease Do not copy or distribute. © 2020 Amgen. All rights reserved

Results(2/2) § SAE attributed to blinatumomab (n=22 cycles) § Neurologic (n=5: confusional status [n=4], transient aphasia [n=1]) and infections (n=2). § Infections (n=5) § All were reversible and did not motivate definitive suspension of blinatumomab in any case. SAE: serious adverse event 7 Do not copy or distribute. © 2020 Amgen. All rights reserved

Conclusion § The first interim analysis of this trial shows that the administration of blinatumomab intercalated with HD chemotherapy cycles is feasible and safe and is associated to a median reduction of MRD levels of 1 logarithm after cycle 3 and 2 logarithms after cycle 6. HD: high dose; MRD: measurable residual disease 8 Do not copy or distribute. © 2020 Amgen. All rights reserved

Grants & Contact Information Funding: This study was sponsored by the PETHEMA Foundation and supported by AMGEN. Supported by grants PI 14/01971 FIS, lnstituto Carlos III, and SGR 225(GRE), Spain. E-mail: jribera@iconcologia. net 9 Do not copy or distribute. © 2020 Amgen. All rights reserved

DOSE REDUCED CHEMOTHERAPY IN COMBINATION WITH BLINATUMOMAB FOR NEWLY DIAGNOSED OLDER PATIENTS WITH PH-NEGATIVE B-PRECURSOR ALL: FIRST RESULTS OF THE BOLD TRIAL Nicola Gökbuget* 1, Andrea Stoltefuß 2, Stefan Schwartz 3, Andreas Viardot 4, Lena Baumann 5, Monika Bruggemann 6, Christoph Faul 7, Mana Wachsmuth 8, Anne Wilke 9, Vladan Vucinic 10, Max Topp 11 1 Dept. of Medicine II, Hematology/Oncology, Goethe University, University Hospital, Frankfurt, 2 Hematology, Evang. Krankenhaus, Hamm, 3 Hematology, Charite Universitätsmedizin , CBF, Berlin, 4 Hematology, Universitätsklinik, Ulm, 5 Department of Medicine II, Hematology/Oncology, Goethe University, University Hospital, Frankfurt, 6 Hamätologie Labor Kiel, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel , 7 Hematology, University Hospital, Tübingen, 8 Hematology, University Hospital, Halle (Saale) , 9 Dept. of Medicine , Hematology/Oncology, Goethe University, University Hospital, Frankfurt, 10 Hematology, University Hospital, Leipzig, 11 Hematology, University Hospital, Würzburg, Germany 10 Do not copy or distribute. © 2020 Amgen. All rights reserved

Introduction § Older patients with ALL are ineligible for unmodified pediatric-based therapies. Even with age adapted, dose reduced regimens early death (ED) is considerable and overall survival (OS) poor. In 412 pts with a median age of 65 (55 -85) yrs treated according to the GMALL Elderly Protocol we observed a CR rate of 75%, with 16% ED; the 3 y OS was 30%. § Thus, further intensification of chemotherapy is no option. ALL: acute lymphoblastic leukemia; CR: complete remission; GMALL: German multicenter study group for adult acute lymphoblastic leukemia; pts: patients; yrs: years 12 Do not copy or distribute. © 2020 Amgen. All rights reserved

Objective(s) § Therefore, the GMALL study group proposed a trial for the European Working Group for Adult ALL (EWALL) in order to evaluate Blinatumomab in combination with chemotherapy in older ALL pts (NCT 03480438) as a potential new standard for this patient group with high medical need. ALL: acute lymphoblastic leukemia; GMALL: German multicenter study group for adult acute lymphoblastic leukemia 13 Do not copy or distribute. © 2020 Amgen. All rights reserved

Method(s)(1/2) § Patient Population: Pts aged 56 - 76 yrs with CD 19 -pos, Ph-neg B-precursor ALL § Primary endpoint: Complete hematologic remission after induction i. e. chemotherapy and one cycle Blinatumomab § Key secondary endpoint: Molecular response § Treatment: § Prephase: dexa (d 1 -5 10 mg/m 2) and cyclo (d 3 -5 200 mg/m 2) § Induction I: dexa, vincristine and idarubicin § Induction II (only if failure after induction I): Cytarabine, Cyclo Blinatumomab I (Pts with CR, CRu, PR or any status after induction II): 28 µg/d, 28 d (dose step 9µg/d to 28µg/d after 1 wk if no CR/CRu) ALL: acute lymphoblastic leukemia; CR: complete remission; CRu: unconfirmed complete remission; d: days; Ph-neg: Philadelphia chromosome -negative; PR: partial response; Pts: patients; wk: week 14 Do not copy or distribute. © 2020 Amgen. All rights reserved

Method(s)(2/2) For consolidation see schema. § Comorbidities were assessed according to Charison Score. § MRD is measured in the central reference laboratory in Kiel with quantitative PCR of clonal immunoglobuline /TCR rearrangements. CR: complete remission; CRu: unconfirmed complete remission; PR: partial response; MRD: minimal residual disease; PCR: polymerase chain reaction; TCR: T-Cell Antigen Receptors; wks: weeks 15 Do not copy or distribute. © 2020 Amgen. All rights reserved

Result(s) (1/4) Included pts: Hospitals: Median Age: Male: Immunophenotype c/pre. B: pro. B: MLL pos: MLL neg: Unknown: Any comorbidity: Myocardial infarction: Vascular disease: Cerebrovasc. Disease: Chronic pulm. Disorder: Diabetes wo end organ d. : Prior tumor wo metast: 20 10 66 (57 -76) yrs 60% 12(60%) 8 (40%) 3 3 2 10 (50%) 2 (10%) 3 (15%) 1 (5%) 2 (10%) 1 (5%) MLL: Mixed-lineage leukemia; neg: negative; pos: positive; pts: patients; pulm: pulmonary. 16 Do not copy or distribute. © 2020 Amgen. All rights reserved

Result(s)(2/4) Induction I Evaluable: CR PR Failure Death: 18 13 (72%) 2 (11%) 1 ( 5%) Induction II Evaluable: CR Failure 2 1 1 Blinatumomab I Evaluable: 11 CR 10 Failure 1 17 CR: complete response; PR: partial response Mol. CR 22 Mol. Fail 33 Low positive 3 3 Not available 5 5 Low positive 1 Mol. CR Mol. Fail Low positive Not available 5 0 4 1 Do not copy or distribute. © 2020 Amgen. All rights reserved

Result(s)(3/4) Results in CR induction I: Mol CR induction I: CR Blinatumomab I: Mol CR Blina I: Pro B-ALL 6/8 0/4 5/5 1/5 vs vs vs c/pre B-ALL 7/10 2/4 5/5 4/4 Follow-up (N=10 pts with MRD result and CR after Blinatumomab I) Mol. CR (N=5): Low. Pos (N=4) Mol. CCR 4, Mol. Relapse* Mol. CCR 2, Low. Pos 1, Mol. Relapse* 1 *Both molecular relapses were pro B-ALL and followed by cytologic relapse CR: complete response; MRD: minimal residual disease; PR: partial response 18 Do not copy or distribute. © 2020 Amgen. All rights reserved

Result(s)(4/4) Toxicities Cycle 1 Blinatumomab (N=8) AE-Term/Grade 1 2 3 4 Total % GOT 1 0 0 0 1 12. 5 Anemia 0 1 0 0 1 12. 5 CRS 2 1 0 0 3 37. 5 Diarrhea 0 1 0 0 1 12. 5 Edema limbs 1 0 0 0 1 12. 5 Gastritis 0 0 1 12. 5 Hypokalemia 1 0 0 0 1 12. 5 Immunoglobulin deficiency 1 0 0 0 1 12. 5 Lymphopenia 0 0 0 3 3 37. 5 Neutropenia 0 0 0 1 1 12. 5 Thromboembolic event 0 1 0 0 1 12. 5 Weight gain 1 0 0 0 1 12. 5 Leukopenia 1 0 2 25. 0 Interruption of cycle 1: N=1 19 AE: adverse event; CRS: Cytokine release syndrome Do not copy or distribute. © 2020 Amgen. All rights reserved

Conclusion(s) § Very low intensity chemotherapy induction induced a surprisingly high proportion of complete remissions § Tolerability and efficacy of the regimen was promising with a high response rate and low mortality. § MRD response was obtained in all pts with CR after Blinatumomab induction. § A proportion of pts - mainly pro-B- ALL - remained MRD positive § Consequent MRD follow-up is required in pts with detectable MRD § Treatment alternatives in pts with molecular relapse have to be defined § Further follow-up and larger patient numbers are required to establish the potential benefit of this regimen in all subtypes of B-prec. ALL: Acute lymphoblastic leukemia; CR: complete response; MRD: minimal residual disease; pts: patients 20 Do not copy or distribute. © 2020 Amgen. All rights reserved

Acknowledgement(s) § This trial is conducted under the sponsor role of the University of Frankfurt. § It is financially supported and supplied with study drug by Amgen. § We thank Lena Baumann and Julian Knaden for data management and study coordination 21 Do not copy or distribute. © 2020 Amgen. All rights reserved