SGN-CD33A: Case Reports of Anti-Leukemic Activity and Bridge to Allogeneic Stem Cell Transplant (SCT) in Patients with Acute Myeloid Leukemia (AML)

Background

CD33 is expressed on the surface of myeloblasts in ~90% of AML, representing a promising, clinically validated target. SGN‑CD33A is an anti-CD33 engineered cysteine antibody conjugated to ~2 molecules of a pyrrolobenzodiazepine (PBD) dimer, a highly potent DNA crosslinking agent. Upon binding, SGN‑CD33A is internalized and transported to the lysosomes where PBD dimer is released through proteolytic cleavage of the linker, crosslinking DNA and leading to cell death.

Methods

A phase 1 dose-escalation study (NCT01902329) evaluating the safety and anti-leukemic activity of SGN-CD33A is ongoing. AML patients (ECOG 0-1) must have relapsed disease after initial remission (CR) of > 3 months or declined induction/consolidation. SGN-CD33A is given IV q3wk up to 4 cycles and optional maintenance for patients with CR/CRi. This report details the experience of 2 patients who received SGN-CD33A, had anti-leukemic benefit, and went to allogeneic SCT. 

Results

Case 1: A 37-year-old male with AML (intermediate risk cytogenetics) achieved CR with standard induction/consolidation May 2013.  He relapsed Dec 2013 and got decitabine before enrolling in SGN33A-001 Jan 2014 (20 mcg/kg).  He had ECOG 1, G4 neutropenia, G3 thrombocytopenia, and 6-8% blasts.  D15 marrow showed a hypocellularity with no evidence of leukemia. He remained pancytopenic and his marrow hypoplastic with no evidence of AML until residual leukemia was identified at 6.6% by flow cytometry in hypocellular marrow Mar 2014. He had a double cord transplant Apr 2014 with fludarabine, cytoxan, and TBI conditioning regimen.  D30 and D100 posttransplant marrow had no AML and 100% donor chimerism. He is now 5 months posttransplant with no AEs related to SGN-CD33A.

Case 2: A 41-year-old male with normal karyotype AML (nucleophosmin cytoplasmic and IDH2 mutations) achieved CR with high-dose cytarabine + idarubicin induction Jul 2013 which was complicated by acute renal failure requiring hemodialysis.  He had 4 cycles of idarubicin + cytarabine consolidation. He relapsed Apr 2014 and enrolled in SGN33A-001 (60 mcg/kg).  He had ECOG 0, G3 neutropenia, and G2 thrombocytopenia. The marrow was 10-20% cellular with 50% CD33+ blasts. D15 marrow was <5% cellular without AML.  He experienced cellulitis with lymphangitis, Staphylococcus aureus bacteremia, and persistent fever with cavitary pulmonary nodules.  He had prolonged pancytopenia; D64 marrow was < 5% with pockets of hematopoiesis.  He had fludarabine and busulfan conditioning regimen and MRD allo HSCT complicated by severe mucositis.  He had neutrophil recovery by D16.  D30 marrow had no AML and 100% donor chimerism.  He is doing well at D75.

Conclusions

These case reports support the anti-leukemic activity of SGN-CD33A and enablement of allogeneic SCT.  This trial is ongoing to define MTD and optimize dose and schedule. Combinations of SGN-CD33A with standard AML and MDS agents are planned.