General AML,   NPM1

Vadastuximab talirine as monotherapy achieves responses and found to be tolerable in CD33 positive AML patients

CD33 is a myeloid differentiation antigen, a transmembrane receptor, expressed on the surface of normal mature or immature myeloid cells and on most Acute Myeloid Leukemia (AML) blasts– it therefore serves as a promising target for antibody-based therapies. Vadastuximab talirine (SGN-CD33A) is a highly potent humanized anti-CD33 antibody-drug conjugate (ADC). Based on previous encouraging preclinical studies, Eytan M. Stein from the Memorial Sloan Kettering Cancer Center, New York, NY, and colleagues conducted a phase I, first-in-human, dose escalation trial (NCT01902329) assessing vadastuximab talirine for patients with CD33-positive AML to evaluate the safety, tolerability, Maximum Tolerated Dose (MTD), activity and pharmacokinetics. The results of the study were reported in Blood in December 2017.

Overall, 131 patients with a median age of 73 years were included from across 14 US cancer centers from July 2013 to February 2016. Of these, 50% had underlying Myelodysplasia (MDS). All patients were administered a maximum of two cycles of vadastuximab talirine. Those who achieved Complete Remission (CR) or Complete Remission with Insufficient Recovery of Counts (CRi) during the first two cycles were entitled for extension treatment every 3 weeks at 5 or 10 µg/kg. A standard 3 + 3 dose escalation design was also implemented, with vadastuximab talirine administered at 5–60 µg/kg on Day 1 of every cycle for 21 cycles. Additional monotherapy expansion cohorts were established in order to explore dose levels in specific subpopulations such as patients on fractioned dosing schedule (at 20 µg/kg on Days 1 and 4 for 21 cycles), patients with Relapsed or Refractory (R/R) NPM1 mutated AML, newly diagnosed, treatment-naïve AML (40 µg/kg), and patients who relapsed after allo-hematopoietic stem cell transplantation (HSCT) (40 µg/kg and 20 µg/kg groups). Dose Limiting Toxicity (DLT) was evaluated during the first cycle of treatment.

Key findings:


  • Dose-dependent rapid elimination of ADC from circulation
  • ADC was not detectable in any patients of the highest-dose group (60 µg/kg) past Day 4
  • Concentration-time profiles were consistent among all cohorts


  • The recommended dose was 40 µg/kg for further studies
  • Two DLTs occurred: Grade 3 pulmonary embolism at the 20 µg/kg dosage level and Grade 4 hypocellular marrow at the 60 µg/kg level
  • Treatment-Emergent AEs (TEAE) in all patients versus the 40 µg/kg cohort: febrile neutropenia (57% vs 72%), thrombocytopenia (44% vs 50%), anemia (38% vs 22%)
  • The most common non-hematologic AEs reported were: nausea, fatigue and diarrhea
  • Across all monotherapy cohorts, the 30- and 60-day mortality rates were 8% and 27%, respectively
  • Expansion Cohorts
    • Fractionated Dosing Cohort (n = 12)
      • One DLT occurred: Grade 3 mucositis
      • Fractioned dosing was recanted, as the single-dose cohort achieved greater safety outcomes
    • NPM1 Mutation Positive Relapsed AML (n = 13)
      • Four patients received allo-HSCT following vadastuximab talirine therapy
    • Older, treatment-naïve AML (n = 27)
      • Two DLTs occurred: Grade 3 decreased DLCO and Grade 3 hematuria
      • No death occurred within 30 days of first dose
    • Post allo-HSCT Relapsed AML (n = 12)
      • In the 40 µg/kg cohort (n = 4) two patients experienced DLTs: Grade 4 hyperbilirubinemia, Grade 4 hypocellular marrow
      • In the 20 µg/kg cohort (n = 8) two DLTs occurred: Grade 4 acute kidney injury, Grade 3 hyperbilirubinemia


  • In the dose finding cohorts (n = 69)
    • The sum of CR and CRi: 19% (95% CI, 10.4–30.1), with 41% blast clearance
  • At the recommended monotherapy dose of 40 µg/kg (n = 18)
    • The sum of CR and CRi rates: 28% (95% CI, 9.5–53.5), with 47% blast clearance
    • MRD-negative rates: CR = 50%, CRi = 67%
  • The median time to full count recovery in patients who achieved CR or CRi:
    • Neutrophil granulocytes: 6.4 weeks (≥1,000/µL)
    • Platelets: 10.6 weeks (≥100,000/µL)
  • Baseline CD33 expression and response
    • CD33 expression in bone marrow (BM) and peripheral blood (PB) samples correlated with the likelihood of achieving blast clearance
      • Odds-ratios: 3.95 (95% CI, 1.31–13.4), P = 0.020 and 3.69 (95% CI, 1.31–11.22), P = 0.016, respectively
    • The addition of NPM1 mutation as a covariate decreased the significance of the association between the presence of CD33 and blast clearance in BM and PB
      • Odds-ratios: 2.38 (95% CI, 0.67–9.21), P = 0.19, and 1.86 (95% CI, 0.54–6.80), P = 0.33

The authors stated that vadastuximab talirine as monotherapy is able to achieve responses with tolerable safety profiles in patients with CD33 positive AML. In general, most non-hematologic AEs were mild to moderate, reversible, even in older patients. However, the authors also mentioned that the phase III CASCADE trial examining vadastuximab talirine in combination with HMAs compared to HMAs alone, was discontinued due to data which indicated a higher rate of deaths, including fatal infections in the vadastuximab talirine containing arm versus the control arm. Nonetheless, “the optimal approach to incorporating vadastuximab talirine into a therapeutic strategy for patients with AML has not yet been determined.”



Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study ( NCT01902329) evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naïve patients. Patients received vadastuximab talirine intravenously on Day 1 (5-60 µg/kg) or on Days 1 and 4 (20 µg/kg) of 21-day cycles. 131 patients (median age 73 years [range, 26-89]) had intermediate I-II (48%) or adverse (34%) risk by ELN classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (Grade 2 pulmonary embolism and Grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AE) were consistent with myelosuppression; non-hematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the CR+CRi rate was 28% (5/18); 50% of patients who responded achieved MRD negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1,000/µL) and 10.6 weeks for platelets (≥100,000/µL). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose is 40 µg/kg.

  1. Stein E.M. et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33 positive acute myeloid leukemia (AML). Blood. 2017 Dec 1. DOI: 10.1182/blood-2017-06-789800. [Epub ahead of print]