Clinical Lymphoma, Myeloma & Leukemia, Vol.22, Suppl.2 - October 2022

Abstracts Clinical Lymphoma, Myeloma & Leukemia October 2022 S318 Mark Chao MD, PhD 2 , Jens-Peter Volkmer MD 2 , Irving Weissman MD 6 1 Stanford University School of Medicine, Stanford, USA. 2 Gilead Sciences, Inc, Foster City, USA. 3 University of Washington School of Medicine, Seattle, USA. 4 Brigham and Women’s Hospital, Boston, USA. 5 Ludwig Cancer Center and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of MedicineMolecular Hematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Stanford, USA. 6 Ludwig Cancer Center and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, USA Co n text: Magrolimab is an antibody blocking CD4 7 , a “don’t eat me” signal expressed on cancer cells, to escape immune surveillance and macrophage-mediated clearance. Preclinical studies found that CD4 7 is critical to RBC homeostasis, with CD4 7 deficiency decreasing RBC half-life. Fc-mediated opsonization also depletes RBCs, raising concerns that potential on-target anemia could result from the use of anti-CD4 7 agents. Several clinical trials demonstrated that magrolimab can be safely administered as monotherapy, with an initial lower “priming” dose yielding transient anemia with compensatory reticulocytosis and no anemia observed at higher maintenance doses. However, the underlying mechanism has not been fully defined. Objecti v e: To describe manageable anemia in magrolimab-treated patients and further investigate the underlying mechanisms in preclinical models. D esig n : Prospective analysis from a ph1 trial of magrolimab+azacitidine (NCT032484 7 9). Complete blood counts (CBCs), peripheral blood, and bone marrow (BM) were collected from patients at prespecified time points. CBCs were measured, and blood and BM samples were analyzed by flow cytometry for CD4 7 expression on RBCs and white blood cells (WBCs). Preclinical modeling studies were conducted with intact and Fc-deficient anti-mouse CD4 7 (MIAP410) and anti-human CD4 7 (magrolimab) antibodies in murine models, including C5 7 BL/6J B-hSIRPA/hCD4 7 mice. Patie n ts: 5 7 patients with HR MDS. I n ter v e n tio n s: Magrolimab IV 1 mg/kg (priming) then 30 mg/kg QW, then Q2W (maintenance). Azacitidine 7 5 mg/m 2 days 1- 7 (each 28-day cycle). Results: Treatment with magrolimab+azacitidine resulted in tolerable anemia that correlated with rapid, near-complete loss of CD4 7 in RBCs but not WBCs. The initial 1-mg/kg priming dose was sufficient for CD4 7 loss, which persisted with subsequent 30-mg/kg maintenance doses. Both findings are consistent with prior clinical observations of magrolimab monotherapy in patients with solid tumors and magrolimab+rituximab in patients with lymphoma. Our preclinical studies with mouse models revealed that CD4 7 removal is mechanistically independent of previously described RBC antigen modulation mechanisms and cellular compartments. Instead, this CD4 7 loss requires anti-CD4 7 cross-linking between RBCs and non-RBCs. Co n clusio n s: These results support the idea that on-target magrolimab-mediated anemia is mitigated by a near- complete loss of RBC CD4 7 . Patients with HR MDS treated with magrolimab+azacitidine had tolerable anemia with priming and maintenance doses. Keywords: MDS, myelodysplastic syndromes, magrolimab, azacitidine, CD4 7 , red blood cells MDS-502 Supportive Care in Low-Risk Myelodysplastic Syndromes: Role of Erythropoiesis Stimulating Agents (ESAs) Claudio Cerchione MD, PhD 1 , Fiorella Alfinito MD 2 , Benedetta Maria Giannini MD 1 , Fabrizio Pane MD 2 , Gerardo Musuraca MD 1 , Giovanni Martinelli MD 1 1 Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy. 2 AOU Federico II, Napoli, Italy Co n text: Erythropoiesis stimulating agents (ESAs) are the frontline treatment in low-risk anemic MDS patients, and an employment of this therapy in the earlier stage of the disease can delay the need for RBC transfusion, hypothetically by slowing the disease course. Macrocytosis is one of the cytological hallmarks of dyserithropoiesis in MDS. An analysis of the erythropoietic response to ESAs therapy in a cohort of anemic non transfusion-dependent MDS patients, enrolled in a retrospective register, RECAMDS, subgroup of Italian register, was performed. Patie n ts: 183 patients, treated with standard-dose ESAs, have been retrospectively analyzed. Data analysis was performed, according to IWG 2006 criteria, at the baseline, after 3 and 6 months of continuous treatment, with a subanalysis of the patients according to WHO and R-IPSS risk stratification. ESAs were started at mean Hb concentration of 9.31 g/dl, mean serum erythropoietin (EPO) concentration: 51 mU/L, after a mean time from diagnosis of 6 months (r.1-118). Results: ORR was 83.6% (153/183); no difference among WHO and IPSS subgroups was found. 132/183 ( 7 2.1%) achieved response after 3 months of treatment, while other 21/183 (11.2%) after 6 months. 19 patients with stable disease (non-responders, according to IWG criteria), in which treatment was continued, achieved response after 9 months. In the macrocytic-responders group, 83.2% exhibited again macrocytosis after 3 months, while 16.8% become normocytic. In the normocytic-responders group, 89.8% exhibited again normocytosis, while 10.2% become macrocytic. In these patients, after 3 months, there was a contemporary worsening in neutropenia and thrombocytopenia, with transfusion-dependence, regarded as first signs of progression of disease. Non-responders were 30/183 (16.3%): in the macrocytic non-responders group 89% exhibited again macrocytosis after 3 months, while 11% become normocytic; in the normocytic group 7 6% exhibited again macrocytosis, while 24% become normocytic. Co n clusio n s: These preliminary data can suggest that, in the majority of MDS patients responsive to ESAs, the increase of Hb concentration occurs mainly due to stimulating erythroid production in MDS clones; in the minority of patients probably it happens due to recruiting residual polyclonal erythropoiesis. It is interesting to note that stimulating effects of ESAs last even when the expression of dysplasia progresses. Keywords: MDS, myelodysplastic syndromes, ESAS, supportive care, erythropoietin

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