TY - JOUR
T1 - Sequential cytarabine and α-particle immunotherapy with bismuth-213-lintuzumab (HuM195) for acute myeloid leukemia
AU - Rosenblat, Todd L.
AU - McDevitt, Michael R.
AU - Mulford, Deborah A.
AU - Pandit-Taskar, Neeta
AU - Divgi, Chaitanya R.
AU - Panageas, Katherine S.
AU - Heaney, Mark L.
AU - Chanel, Suzanne
AU - Morgenstern, Alfred
AU - Sgouros, George
AU - Larson, Steven M.
AU - Scheinberg, David A.
AU - Jurcic, Joseph G.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi- lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi- lintuzumab was achieved after partial cytoreduction with cytarabine. Conclusions: Sequential administration of cytarabine and 213Bi- lintuzumab is tolerable and can produce remissions in patients with AML.
AB - Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle-emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi- lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi- lintuzumab was achieved after partial cytoreduction with cytarabine. Conclusions: Sequential administration of cytarabine and 213Bi- lintuzumab is tolerable and can produce remissions in patients with AML.
UR - http://www.scopus.com/inward/record.url?scp=78049456138&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=78049456138&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-10-0382
DO - 10.1158/1078-0432.CCR-10-0382
M3 - Article
C2 - 20858843
AN - SCOPUS:78049456138
SN - 1078-0432
VL - 16
SP - 5303
EP - 5311
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -