Gemtuzumab Ozogamicin as Part of Reduced-Intensity Conditioning in Patients with Relapsed or Refractory Acute Myeloid Leukemia - Results of a Phase I/II Trial.

Gemtuzumab ozogamicin (GO) has been associated with an increased risk of liver sinusoidal obstruction syndrome (SOS) when applied within three months before or after allogeneic stem cell transplantation. In addition, excess of liver toxicity has been observed when GO was used directly before conventional intensive preparative regimens. We hypothesized that GO might be safe and effective as part of a fludarabine-based reduced-intensity conditioning regimen. 30 patients relapsing after conventional induction chemotherapy (n=17) or after previous transplantation (autologous n=3; allogeneic n=10) have been included in a prospective phase I/II trial. Per protocol the preparative regimen contained 6 mg/sqm and 3 mg/sqm GO on day-21 and day-14 followed by fludarabine 120 mg/sqm, 200 or 800 cGy total-body irradiation (TBI; depending on age and pretreatment) and stem cell infusion during GO-induced aplasia. Five patients who had previously undergone TBI received melphalan 140 mg/sqm. GvHD prophylaxis was performed with tacrolimus (starting day-1) and mycophenolate mofetil (1.5g BID from day 0). Four patients with progressive disease after GO did not proceed to conditioning therapy and went off study. A reduction of marrow blast counts after GO monotherapy was achieved in 15/30 patients (50%). In 11 cases without response to GO, an additional salvage regimen containing anthracyclines and high-dose cytarabine was administered before conditioning therapy and transplantation. 26 patients received G-CSF mobilized peripheral blood progenitor cells from matched-sibling (n=6) or unrelated donors (n=20). Primary engraftment was observed in all cases. With a median follow-up of 20 months (range 6–55) only one patient experienced sinusoidal obstruction syndrome which was reversible after treatment with defibrotide. Grade II-IV acute GvHD occurred in 15 patients (54%). Nine patients are alive in complete remission. Reasons for death in the other patients were relapse/progression (n=10) and GvHD/Infection (n=7). The probability of overall and disease-free survival at two years for patients having received a transplant is 38% and 32%, respectively. Blast reduction after GO was associated with a superior disease-free survival (48%, p=0.1). These data suggest that GO can be integrated into reduced-intensity conditioning therapy before allogeneic stem cell transplantation in patients with relapsed AML. Refractory patients with no response to GO monotherapy have a low chance of cure and should probably receive other combination therapies.