ARTHUR FRANKEL :  FRIDAY 31 MARCH 2006, 08:30

Diphtheria toxin-interleukin 3 fusion protein therapy of patients with elderly or relapsed/refractory acute myeloid leukemia (AML)

Arthur Frankel
Internal Med, Hematology/ Oncology, Scott & White Hospital, 76508 Temple, USA

Background: A recombinant protein composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin 3 (IL3). DT388IL3 binds to IL3 receptors on leukemic progenitors; the toxin is internalized and enzymatically inactivates protein synthesis leading to programmed cell death. We prepared a clinical batch and obtained FDA approval for a phase I study. Patients and Methods: Relapsed/refractory or elderly (>70 years) AML patients with normal organ function and low anti-DT antibody titers were consented and given DT388IL3 on a MWF for 2 weeks. Premedication was hydrocortisone, acetaminophen, and diphenhydramine. 13 patients received all 6 doses. Results: 19 patients have been treated as of 2/06 (9 males and 10 females). Median age was 58 years. 1 patient - de novo AML; 8 patients - 2nd relapse; 6 patients - 3rd relapse and 4 patients - refractory AML. 1 patient each received an autologous stem cell transplant (SCT), and an allogeneic SCT. Cytogenetics were unfavorable in 3, intermediate in 11 and not done in 5. 1 patient each had MDS-related AML and treatment-related AML. Drug-related side effects were mild and transient including grade 3 fever, grade 2 hypotension, chills and hypoalbuminemia. Responses seen to date have been transient including a reduction in bone marrow blast index (% cellularity x fraction blasts) of pretreatment 40%, 70%, 36% and 40% converting to 8%, 4%, 4% and 4% on day 15. Conclusions: The preliminary data suggests mild toxicity with biological activity. Dose escalation is planned as per protocol.

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