Gemtuzumab Ozogamicin (Mylotarg®) as Part of Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed Acute Myeloid Leukemia.

Gemtuzumab ozogamicin (GO) has been successfully used in older patients with relapsed CD33+ acute myeloid leukemia. Retrospective analyses suggest that the use of GO within a few months before or after hematopoietic stem cell transplantation (HCT) is associated with a increased risk for sinusoidal obstruction syndrome (SOS) or veno-occlusive liver disease (VOD). Ongoing studies investigate the use of GO in the induction and post-remission therapy of AML patients. We hypothesized that GO might be safe and effective as part of a reduced intensity conditioning regimen containing fludarabine and total-body irradiation (TBI)

Fifteen patients relapsing after conventional induction chemotherapy (n=9) or after previous transplantation (autologous n=3; allogeneic n=3) were included so far. The last twelve patients were treated within an ongoing phase II trial. The preparative regimen contained 6 mg/m² and 3 mg/m² GO on day −21 and day −14 before allogeneic transplantation. Patients who responded to GO treatment and were below the age of 60 (n=8) received fludarabine 120 mg/m² and 800 cGy TBI (n=6) during GO-induced aplasia followed by allogeneic HCT. Patients older than 60 years or those with relapsing AML <12 months after the first transplant received 200 cGy TBI (n=7). Tacrolimus and mycophenolate mofetil was administered as GvHD prophylaxis in all patients. Two patients with refractory disease did not undergo transplantation. Six patients (40%) had a complete or partial response and directly proceeded to allogeneic transplantation. In seven cases without response to GO, an additional salvage regimen was directly followed by conditioning therapy and transplantation. Patients received G-CSF mobilized peripheral blood progenitor cells from matched-sibling (n=4) or unrelated donors (n=9) with a maximum of 1 allele mismatch (9/10). Primary engraftment was observed in all patients. Only one patient experienced grade 4 hyperbilirubinemia associated with sepsis and death on day +11. Grade I liver toxicity was observed in four patients. With a median follow-up of 10 months (range 1−48), no case of SOS, VOD or delayed liver toxicity was documented. Grade II–IV acute GvHD occurred in 7 patients (54%). Out of seven patients alive, six are still in complete remission. Reasons for death in the other patients were leukemia relapse (n=6) and acute GvHD (n=2). Patients who responded to GO had a significantly higher probability of disease-free survival (67%) at one year than patients whose blast counts could not be reduced by GO treatment (0%, p=0.007).

These data suggest, that GO can be combined with a TBI-containing, fludarabine-based conditioning regimen before allogeneic HCT in patients with relapsed AML. No increased incidence of VOD has to be expected even in recipients who had undergone previous conditioning therapy and transplantation. Nevertheless, additional chemotherapy during aplasia before allogeneic transplantation is required in 60–70% of patients who do not respond to GO. For responding patients the combined regimen is associated with minimal toxicity and a considerable chance for long-term cure.