Gemtuzumab Ozogamicin with Donor Leucocyte Infusions Is Safe and Effective Therapy for a Subgroup of Relapsed Acute Myeloid Leukaemia and Myelodysplastic Syndrome Following Allogeneic Haemopoietic Stem Cell Transplantation (HSCT).

Gemtuzumab Ozogamicin (GO) is an anti-CD33 antibody linked to the cytotoxic antibiotic calicheamycin. Its use in AML and acute promyelocytic leukaemia has been previously described and its hepatotoxic side effects highlighted. Haemopoietic stem cell transplantation is another modality used in the treatment of relapsed AML with graft versus leukaemic effect being implemented by T cells that are effective against the tumor specific antigens. However relapse can occur despite the presence of 100% donor derived T cells. We report prolonged disease free survival (DFS) following the use of GO/DLI. Patients with relapsed or refractory leukaemia AML (n=28) and myelodysplasia (n=6, RAEB1 n=5, RAEB2 n=1), median age 52 yrs (19–66) received treatment with gemtuzumab ozogamicin (GO) between January 2001 and February 2004 at King’s College Hospital. Six had previously untreated AML or MDS, 17 had AML/MDS in first relapse, 4 in second relapse, 6 were refractory and 1 was in second remission. Seventeen patients received GO with FLAG ± Idarubicin and 17 had GO alone. Complete remission (CR) was similar in both groups( 47% vs. 41%respectively). Twenty seven patients received single dose, 5 patients received 2 and 2 patients received 3 doses of GO. Twenty six patients received 9mg/m², 4 received 6mg/m², 3 at 3mg/m² and 1 at 4.5mg/m². Following GO 5 patients received conventional conditioning allogeneic HSCT (AlloHSCT), 8 received reduced intensity conditioning (RIC-HSCT) and 1 had autologous rescue. HSCT was done at a median time of 37 days (17–444) post-GO. Six out of 11 patients who underwent HSCT post GO with no DLI are alive in CR, median 810d (120–1080). Hepatotoxicity with bilirubin elevation grades 2–4 (NCI toxicity criteria)occurred in 14 patients associated with elevated AST grades 2–4 in 8 patients and hepatic veno-occlusive disease in 4 patients. Pulmonary haemorrhage occurred in 3 patients, contributing to death in one. Direct anti-globulin test positivity was observed in 6 patients causing significant haemolysis in 4.

Eight patients who relapsed following HSCT received GO followed by donor leucocyte infusion. Blasts from these patients were mean 75.5% (85% median)CD33⁺. Three of the eight patients achieved complete remission, 2 are alive 240 and 810d post GO. Two other patients underwent repeat RIC-HSCT post-GO followed by DLI, both achieved CR, and 1 is alive at 990d. Chimerism data available for 8 patients showed 0–56% donor derived haemopoiesis pre treatment. Donor derived CD3+ cells were 26%and 47% in two patients and 100% in 2 patients pre GO/DLI. In the former two patients the first did not respond to this treatment, the second became 100% donor in the unfractionated bone marrow and in CD3+ fraction. In the latter two, unfractionated bone marrow was 0% donor derived and 56% donor derived pre treatment with these increasing to 77% and a 100% donor derived respectively with the CD3+ fraction remaining 100% donor. Five of these 8 patients acheived CR.Overall 13 patients (31.4%) achieved CR, 9 (25.7%) are alive 120–1080 days post-GO, median 810d. The overall median survival post-GO was 76 days (2–1080).

Our results indicate that gemtuzumab ozogamicin in combination with DLI can benefit the subgroup of patients with AML /high risk MDS who have relapsed post haemopoietic stem cell transplant.