PRACTICE AID Guide to Treatment Role of Antibodies in Acute Leukemia: Focus on Transplant-Eligible Populations

Acute Myeloid Leukemia DRUG STATUS TARGET DOSE

EU EMA approved: In combination with daunorubicin and Induction: 3 mg/m2 (up to 5 mg/m2 in EU and 4.5 mg/m2 in US) for pts aged ≥15 y with previously untreated, on d 1, 4, and 7 in combination with daunorubicin and cytarabine de novo CD33+ AML, except APL CD33 Consolidation: 3 mg/m2 (up to 5 mg/m2 in EU and 4.5 mg/m2 in US) Gemtuzumab US FDA approved: Newly diagnosed CD33+ AML in adults and 1,2 on d 1 in combination with daunorubicin and cytarabine ozogamicin pediatric pts aged ≥1 month; R/R CD33+ AML in adults and Please consult label for single-agent dosing and dosing in R/R AML. pediatric pts aged 2 y

Phase 3 SIERRA study CD45 Adults aged ≥55 y with active R/R AML, adequate organ Dosimetry directed (SIERRA study) Iomab-B3 function, and related/unrelated matched donor (BC8 mAb linked to radioisotope iodine-131) Acute Lymphoblastic Leukemia

EU EMA approved: Adults with R/R CD22+ B-cell ALL; adults Cycle 1 dose: 0.8 mg/m2 on d 1; 0.5 mg/m2 on days 8 and 15 for 21 d 2 Inotuzumab with Ph+ R/R B-cell ALL who failed treatment with at least one TKI CD22 Patients in CR/CRi: 0.5 mg/m on days 1, 8, and 15 for 28 d ozogamicin4,5 US FDA approved: Adults with R/R CD22+ B-cell ALL Patients not in CR/CRi: Use cycle 1 dose for 28 d

EU Dose: By patient’s weight (≥45 kg = 9 mcg/d on d 1-7 and 28 mcg/d on EU EMA approved: Adults with B-cell ALL who are in d 8-28; <45 kg = 5 mcg/m2/d on d 1-7 and 15 mcg/m2/d on d 8-28); induction remission with MRD of ≥0.1% CD19 for 28 d with 14 d break; consolidation is same for up to 5 cycles for CR/CRh 6,7 US FDA approved: Adults with B-cell ALL who are in rst or US Dose: By patient’s weight (≥45 kg = 28 mcg/d; <45 kg = 15 mcg/m2/d); second complete remission with MRD of ≥0.1%; R/R B-cell ALL induction for 28 d with 14 d break; consolidation is same for up to 4 cycles

Notes for the Transplant Setting8,9 • Although ADCs have been associated with increased risk for hepatic toxicity (such as VOD) post-HSCT, and are among the risk factors for post-transplant VOD some evidence shows that careful selection of conditioning regimens with lower risk of hepatotoxicity can mitigate the risk of VOD when using ADCs • Overall, when using ADCs in patients with acute leukemia proceeding transplant, close monitoring for VOD and early medical interventions are warranted • In ALL, limiting the number of cycles and avoiding conditioning regimens containing two alkylating agents, as well as close monitoring for the occurrence of VOD, may limit VOD and improve long-term outcomes • In AML, adopting a 60-day period from the last dose to transplant may also mitigate risk of VOD

Access the activity, “Antibody Therapy in Acute Leukemia: Understanding Clinical Considerations for Use in Conjunction With HSCT,” at PeerView.com/BYH40 PRACTICE AID Guide to Treatment Role of Antibodies in Acute Leukemia: Focus on Transplant-Eligible Populations

How Novel Antibody Technologies Target Antigens and Novel Antibodies in AML Work in Acute Leukemia Recent developments in AML/ALL have included the approvals of ADCs [gemtuzumab and Gemtuzumab ozogamicin inotuzumab ozogamicin], bispecific antibodies [blinatumomab], as well as continuing 225Ac-Lintuzumab (Actimab-A) research into other ADCs, radioimmunoconjugates, and bispecific agents CD33 AMG 330 (BiTE CD33/CD3) AMG 673 (BiTE CD33/CD3) Antibody Hu7007 Apoptosis XmAb (CD3/CD123) CD123 ADC targets and binds MGD006 to cell surface antigens IMGN632 on tumor cells Multiple Cytotoxin Linker Cytotoxins antigen AML released 131 targets and cell CD45 I apamistamab (Iomab-B) agents ADC-receptor CD47 Magrolimab complex ADCs internalized AMG 427 FLT3 CD70 Cusatuzumab ADCs use a chemical linker to connect cytotoxins, such as chemotherapy, with an antibody targeting a speci c antigen Potential to selectively kill Target Antigens and Novel Antibodies in ALL cells and minimize side eects

Conventional IgG Asymmetric Bispeci c Antibody IgG Antibody Bispeci c antibodies dier in A A Pro-B Pre-B1 Immature B Mature B Plasma Antigen Antigen structure and mechanism from A Heavy B IgM chain conventional antibodies IgM IgG B B Light Light chain chain CD19 Bispeci c T-cell engaging CD3 T cell CD22 agents (BiTEs) are the farthest along in clinical development

CD20 BiTEs Redirected CD10 lysis How BiTEs work: Recruitment Ig / of T cells or via binding to tumor Target antigen Cytoplasmic Tumor cell cell surface antigens, as well as D-J VDJ V-J light Surface CD19 Tumor cell to immune cells

ADC: antibody-drug conjugates; AML: ; APL: acute promyelocytic leukemia; BiTEs: bispecific T-cell engagers; CR: complete remission; CRh: complete response with partial recovery of peripheral blood counts; CRi: complete response with incomplete hematologic recovery; EMA: European Medicines Agency; HSCT: hematopoietic stem cell transplantation; mAB: monoclonal antibodies; MRD: minimal residual disease; Ph: Philadelphia chromosome; R/R: relapsed/refractory; VDJ: variability, diversity, and joining; VOD: veno-occlusive disease. 1. Mylotarg (gemtuzumab ozogamicin) Prescribing Information. http://labeling.pfizer.com/ShowLabeling.aspx?id=9548. 2. Mylotarg (gemtuzumab ozogamicin) Product Information. https://www.ema.europa.eu/en/documents/product-information/mylotarg-epar-product- information_en.pdf. 3. https://clinicaltrials.gov/ct2/show/NCT02665065. 4. Besponsa (inotuzumab ozogamicin) Prescribing Information. http://labeling.pfizer.com/ShowLabeling.aspx?id=9503&format=PDF. 5. Besponsa (inotuzumab ozogamicin) Product Information. https://www.ema.europa.eu/en/documents/product-information/besponsa-epar-product-information_en.pdf. 6. Blincyto (blinatumomab) Prescribing Information. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf. 7. Blincyto (blinatumomab) Product Information. https://www.ema.europa.eu/en/documents/product-information/blincyto-epar-product-information_en.pdf. 8. Kantarjian H et al. Lancet Hematol. 2017;4:e387-398. 9. Lambert J et al. Haematologica. 2019;104:113-119. Access the activity, “Antibody Therapy in Acute Leukemia: Understanding Clinical Considerations for Use in Conjunction With HSCT,” at PeerView.com/BYH40