Anti-CD123 Targeted Therapy with Talacotuzumab in Advanced MDS and AML after Failing Hypomethylating Agents - Final Results of the Samba Trial

Introduction Recently, progress has been made in the treatment of patients with higher risk myelodysplastic syndromes (HR MDS) and acute myeloid leukemia (AML). Nevertheless, patients failing hypomethylating agents (HMA) have a dismal prognosis and very limited treatment options. Targeting CD123 on leukemic stem cells (LSC) is one promising approach in MDS and AML. Talacotuzumab (TAL, JNJ-56022473) is an IgG1 monoclonal antibody targeting CD123 preferentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by natural killer cells (NKs). Aim The SAMBA trial, a phase II study of the German and French MDS study groups within the EMSCO network assessed the overall hematological response rate after 3 months of single agent TAL treatment in AML or HR MDS patients failing hypomethylating agents (HMAs). Methods TAL was given IV at a dose of 9 mg/kg once every two weeks for a total of 6 infusions, responders received up to 20 additional infusions. After the first 3 months, overall hematological response rate (either CR, PR, marrow-CR, HI, SD) was evaluated by bone marrow biopsy. The study was accompanied by an immune monitoring via flow cytometric analysis to investigate the distribution of T- and NK cells in peripheral blood (PB) and bone marrow (BM) at the time of screening and during therapy in comparison with healthy, age-matched controls. Results 24 patients (19 AML and 5 HR MDS) with a median age of 77 (range 71-90) years, who either failed to achieve complete- (CR), partial response (PR), hematological improvement (HI) or relapsed after HMA therapy were included in the study. After TAL administration, 14 patients could be assessed for response after 4 infusions and 10 patients after 6 infusions. The overall response rate (ORR) was 20.8% including 1 complete remission (CRi), 1 patient with hematologic improvement (HI-E) and additionally 3 patients with disease stabilization. The median duration of response in these patients was 3 months (range 3-14 months). Two patients are still on treatment, one patient despite losing objective response (14 months) and one patient with disease stabilization (13 months). The median overall survival for the entire cohort of patients was 3.2 months (range 0.4-11.2 months). In 10 patients (41.6%), therapy with TAL resulted in grade 3/4 infusion related side effects (pneumonia, n=1; infusion-related reaction, n=8; septic shock, n=1). Before treatment initiation, patients had lower levels of CD56dim NK-cells in PB (82% vs. 89% of NK-cells; p=0.069) expressing significantly more inhibiting NK-cell receptors like KIR2DL2 (8.8% vs. 3.2% of NK-cells; p We could not detect any difference in NK-cell levels in responding patients compared to non-responders. Interestingly, pre-treatment expression (MFI and percentage) of CD123 on immature myeloid derived suppressor cells (iMDSC) was higher in responders than in non-responders (p Conclusion Single agent TAL has limited efficacy in patients with advanced myeloid malignancies failing HMA. Expression of CD123 on immature MDSCs might serve as a biomarker of response for future anti-CD123 targeted approaches. Disclosures Gotze:Celgene: Honoraria, Research Funding; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017. Kronke:Celgene: Honoraria. Middeke:Roche: Membership on an entity9s Board of Directors or advisory committees; Abbvie: Membership on an entity9s Board of Directors or advisory committees; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Fenaux:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ades:JAZZ: Honoraria; Takeda: Membership on an entity9s Board of Directors or advisory committees; silent pharma: Consultancy; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Platzbecker:Celgene: Research Funding.