Low Incidence of Hepatic Veno-Occlusive Disease after Fractionated Doses of Mylotarg and Autologous or Allogeneic Stem Cell Transplantation.

Background. Gemtuzumab ozogamicin (GO, Mylotarg®) is a humanized calicheamicin-conjugated monoclonal antibody targeted to the CD33 antigen present on myeloblasts. A 28% response rate in acute myeloblastic leukaemia (AML) in first relapse was reported in phase 2 single agent trials using Mylotarg at a dose of 9 mg/m² for two doses at 14 days interval. Significant hepatotoxicity was observed and an increased risk (up to 60%) of developing veno-occlusive disease (VOD) was also reported in patients receiving stem cell transplantation (SCT) after GO exposure. Risk of VOD was correlated with a short interval, less than 3,5 months from GO administration to SCT. We report here the feasibility of an intensive consolidation therapy followed by autologous or allogeneic SCT in patients with AML in complete remission after a reduced and fractionated salvage therapy with GO.

Patients and methods. We retrospectively collected the results from 10 consecutive patients (median age 47 years; 18 years to 62 years) treated in 4 haematological centers. All patients received 3 infusions of GO 3 mg/m²/d at day 1, day 4 and day 7 during the induction course. Consolidation modalities and conditioning regimens before HSCT were adapted in each center.

Results. Eight patients were in relapse (first relapse, n=4; second and subsequent relapses, n=4) and 2 were primary refractory to induction therapy. After GO salvage therapy, 6 patients achieved a complete remission (CR) and 4 a CR without normalization of the platelets counts (CRp). A grade 1 toxicity and a non severe VOD were recorded during salvage therapy. Consolidation therapy was administered in 6 cases (based on Ara-C chemotherapy in 5 cases and GO administration (3 mg/m² day 1) in 1 case). Five patients received an allogeneic SCT (genoidentical donors n=2, phenoidentical donors n=3, one of those after a non myeloablative conditioning regimen) and five patients received an autologous SCT after a conditioning regimen with busulfan and melphalan. Median interval between the last chemotherapy and the graft was 47 days (16 to 61 days) and median interval from the last dose of GO and the graft was 108 days (16 to 221 days). Three cases (30%) of hepatic toxicity were recorded (grade 1, n=1; grade 2, n=1; grade 3, n=1), including 2 cases with VOD (20%), one of them confirmed by liver biopsy. The two patients with VOD were successfully treated with defibrotide and normalization of the hepatic tests was obtained. In both cases, the conditioning regimen was TBI/EDX and the interval from the last GO infusion to SCT was short (30 days and 16 days). Of note, the patient who experienced hepatic toxicity during the fractionated induction course did not experienced hepatic toxicity during the intensive SCT phase. Overall, median DFS and OS post SCT were 6.4 months and 8.6 months respectively.

Conclusion. This retrospective study argues in favour of a lower hepatotoxicity with fractionated doses of GO leading to a lower risk of VOD when stem cell transplant is used as post remission therapy.