Targeted radiotherapy in the conditioning prior to haematopoietic stem cell transplantation: Results of a phase I trial using an yttrium-90-labelled anti-CD66 murine monoclonal antibody demonstrating consistently high BM uptake (2006)

We report the results of a phase I clinical trial using an yttrium-90 (Y-90) radiolabelled anti-CD66 IgG1 murine monoclonal antibody (TheraPharm GmbH) with conditioning therapy for patients receiving either an autologous or reduced intensity (RIC) allogeneic stem cell transplant (SCT) for myeloma or AML. This was a radiation dose escalation study with five patients at each radiation dose level of 5, 10, 25 and 37.5 MBq/kilogram lean body weight of recipient. Patients initially received indium-111-labelled anti-CD66 for biodistribution and dosimetry. Patient Characteristics: Ages 21-67 yrs (mean 56 yrs); 16 male, 4 female; disease indication for transplant: myeloma 18, poor risk AML 2. Autologous transplant 16; RIC-allogeneic 4. Patients received the therapeutic dose of radiation on day −14, for autologous SCT they also received melphalan 200 mg/m2 on day −2; allogeneic SCT patients received a combination of fludarabine, melphalan and CAMPATH from day −8. Results: Excellent bone marrow targeting was seen in all patients with a 2-10 fold excess of radiation delivered to the bone marrow as compared with the liver. There was a linear relationship between the infused dose of Y-90 and the estimated radiation dose delivered to the BM. Mean absorbed radiation doses were: bone marrow 10.23 ± 1.8 cGy/MBq; liver 2.67 ± 2.0 cGy/MBq; spleen 7.10 ± 3.75 cGy/MBq. Total absorbed radiation doses at each Y-90 dose level are shown in Table 1). No additional toxicity due to the additional radiation was seen. Engraftment: neutrophils >0.5 by day +13.8 (range 11-22); platelets >50 by day +12.7 (range 10-22), no graft failures. In one patient with myeloma, focal uptake of radiolabelled antibody was seen at sites of disease activity suggesting in vivo targeting of myeloma. This is consistent with our finding of CD66 antigen expression by malignant plasma cells as shown by flow cytometry. There was a trend to greater disease response as the radiation dose increased, with a greater proportion of patients at the higher radiation dose levels achieving a CR. Conclusions: The radiolabelled anti-CD66 monoclonal antibody showed consistently excellent BM targeting and very low uptake by non-haematopoietic organs. Up to 30 Gy of radiation was delivered to the BM with no additional toxicity to other organs. Phase II studies are under way using the Y-90-labelled anti-CD66 in RIC-allogeneic SCT protocols and for autologous SCT for myeloma.Table 1Organ DosimetryOrgan Dose in (Gy)Dose level (MBqkg)Bone MarrowLiverSpleen54.11.41.1109.11.32.42515.63.712.637.525.07.45.1 Open table in a new tab We report the results of a phase I clinical trial using an yttrium-90 (Y-90) radiolabelled anti-CD66 IgG1 murine monoclonal antibody (TheraPharm GmbH) with conditioning therapy for patients receiving either an autologous or reduced intensity (RIC) allogeneic stem cell transplant (SCT) for myeloma or AML. This was a radiation dose escalation study with five patients at each radiation dose level of 5, 10, 25 and 37.5 MBq/kilogram lean body weight of recipient. Patients initially received indium-111-labelled anti-CD66 for biodistribution and dosimetry. Patient Characteristics: Ages 21-67 yrs (mean 56 yrs); 16 male, 4 female; disease indication for transplant: myeloma 18, poor risk AML 2. Autologous transplant 16; RIC-allogeneic 4. Patients received the therapeutic dose of radiation on day −14, for autologous SCT they also received melphalan 200 mg/m2 on day −2; allogeneic SCT patients received a combination of fludarabine, melphalan and CAMPATH from day −8. Results: Excellent bone marrow targeting was seen in all patients with a 2-10 fold excess of radiation delivered to the bone marrow as compared with the liver. There was a linear relationship between the infused dose of Y-90 and the estimated radiation dose delivered to the BM. Mean absorbed radiation doses were: bone marrow 10.23 ± 1.8 cGy/MBq; liver 2.67 ± 2.0 cGy/MBq; spleen 7.10 ± 3.75 cGy/MBq. Total absorbed radiation doses at each Y-90 dose level are shown in Table 1). No additional toxicity due to the additional radiation was seen. Engraftment: neutrophils >0.5 by day +13.8 (range 11-22); platelets >50 by day +12.7 (range 10-22), no graft failures. In one patient with myeloma, focal uptake of radiolabelled antibody was seen at sites of disease activity suggesting in vivo targeting of myeloma. This is consistent with our finding of CD66 antigen expression by malignant plasma cells as shown by flow cytometry. There was a trend to greater disease response as the radiation dose increased, with a greater proportion of patients at the higher radiation dose levels achieving a CR. Conclusions: The radiolabelled anti-CD66 monoclonal antibody showed consistently excellent BM targeting and very low uptake by non-haematopoietic organs. Up to 30 Gy of radiation was delivered to the BM with no additional toxicity to other organs. Phase II studies are under way using the Y-90-labelled anti-CD66 in RIC-allogeneic SCT protocols and for autologous SCT for myeloma.