Induction with Combined Modality Therapy Followed by Immunomodulated Post Remission Therapy for Newly Diagnosed Acute Myeloid Leukemia (AML).

Targeted modalities are playing a an increasing role in modern oncology. We have previously demonstrated that the unconjugated humanized anti-CD33 monoclonal antibody, HuM195 has activity in the setting of relapsed AML. Given these results, we designed a clinical trial investigating whether antibody therapy can be combined with other therapeutic approaches including dose intensive chemotherapy and drug/growth factor immunomodulation as the initial therapy for adults with AML and whether such patients can safely proceed to stem cell transplantation. Patients in this study were treated with MEC (mitoxantrone 8 mg/m², etoposide 80 mg/m², and cytarabine 1 gm/m² daily for 6 days). HuM195 was administered for 4 days at a dose of 12 mg/m² on days 6–9 and days 19–22. GM-CSF (250 ug/m²/day) was begun on day 8 and continued until neutrophil recovery. Patients who achieved CR and had a suitable related donor proceeded directly to allogeneic stem cell transplantation (SCT). Others received two additional cycles of high-dose cytarabine followed by autologous SCT augmented by combination cyclosporin and GM-CSF in an effort to induce an autologous graft versus leukemia (GvL) effect. Thirty patients have been treated to date (15 patients with de novo AML; 15 patients with secondary AML). The median age was 51 years (range 24–71). Nineteen of the 28 evaluable patients (68%) achieved CR with 14 of the 15 (93%) de novo AML patients achieving a CR. Three deaths from uncontrolled infection occurred during induction. In patients achieving CR, the median time to recover an ANC > 500/mm³ was 23 days (range 20–36) and a platelet count > 20,000/mm³ was 17 days (range 12–42). Four patients proceeded directly to allogeneic stem cell transplantation without any consolidation therapy and three remain free of disease with a median follow-up of 24 months. One patient is too early for evaluation. Five patients went on to autologous stem cell transplant (AuSCT) and two remain in remission after 13 and 24 months. Three patients relapsed after AuSCT. Two expired from refractory leukemia, and one was salvaged with allogeneic SCT. Among the AuSCT patients, the median time to recovery of the ANC > 500/mm³ and platelet count > 20k/mm³ was 7 days (range 1–9) and 7.5 days (range 5–22), respectively, comparable to patients who received standard induction regimens. There was no clinical evidence of graft verses host disease in the AuSCT patients. No evidence of veno-occlusive disease was observed after either autologous or allogeneic transplantation. Preliminary results suggest combined modality therapy is feasible and well-tolerated as initial therapy for AML. Patients are able to receive dose intensive consolidation therapy including transplantation safely after the use of an intensive induction with combined modality therapy incorporating HuM195. All patients who underwent an allograft after induction remain in remission with two year follow up. Further follow-up is needed to determine the effect on long term outcomes.