Experience with IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Frontline Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

BACKGROUND: BPDCN is a rare, aggressive hematologic malignancy characterized by historically poor overall survival and limited therapeutic options. Despite the recent approval of tagraxofusp-erzs for BPDCN, outcomes remain suboptimal for many patients. Additionally, patients with BPDCN are older and often have co-morbidities at baseline, preventing them from receiving tagraxofusp-erzs. Therefore, novel therapies are needed in the frontline setting for patients with BPDCN. Overexpression of CD123 (IL-3Rα) is present in all BPDCN cases, thereby establishing this surface marker as a target for therapeutic intervention. IMGN632 is a CD123-targeting ADC, comprised of a high-affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. IMGN632 has demonstrated favorable safety and promising clinical activity in relapsed/refractory (R/R) BPDCN [Blood (2020) 136 (Supplement 1): 11-13], leading to the FDA granting IMGN632 Breakthrough Therapy Designation (BTD) for R/R BPDCN (Oct 2020). Following BTD and alignment with FDA, a pivotal cohort in frontline (no prior systemic treatment) BPDCN patients was initiated in addition to a continuing cohort of patients with R/R disease, where we have enrolled 33 patients to date. Here we report the initial experience of three frontline patients who are not part of the pivotal cohort. METHODS: IMGN632 was administered IV at a dose of 0.045 mg/kg on day 1 of a 21-day cycle to all patients. Efficacy was assessed using modified Severity Weighted Assessment Tool (for skin lesions), PET/CT, and blast percentage in bone marrow aspirates. The response criteria were adapted from established BPDCN criteria (Pemmaraju NEJM 2019). RESULTS: Three patients with frontline BPDCN (no prior systemic therapy) received IMGN632. All three of these frontline patients achieved a clinical complete remission (CRc). Patient 1 was a 79yo woman who presented with skin, nodal, and extensive bone marrow disease (80% involvement). After one dose of IMGN632, she cleared her bone marrow (0%), and after 3 cycles, her nodal lesions and skin lesions resolved to achieve a CRc. Upon complete response, treatment was held due to patient co-morbidities. With just 3 cycles of IMGN632, this patient achieved duration of response (DOR) of 10.7 months without further therapy. Patient 2 was a 67yo man who had extensive skin disease covering >20% of the body; over several cycles, he achieved a PR then a CRc and