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) cytarabine 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 Blinatumomab 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 inotuzumab ozogamicin 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 gemtuzumab ozogamicin 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) ADC targets and binds CD123 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 specic antigen Potential to selectively kill cancer Target Antigens and Novel Antibodies in ALL cells and minimize side eects Conventional IgG Asymmetric Bispecic Antibody IgG Antibody Bispecic 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 Bispecic 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: acute myeloid leukemia; 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.