M195, a mouse
monoclonal antibody reactive with the early myeloid
antigen CD33, has been shown to target
leukemia cells in patients and to reduce large leukemic burdens when labeled with 131I. A
complementarity-determining region-grafted, humanized version (
HuM195) has demonstrated similar targeting of
leukemia cells without immunogenicity. We have studied two applications of
therapy with 131I-M195. First, to intensify
therapy prior to
bone marrow transplantation (BMT), we combined 131I-M195 with
busulfan and
cyclophosphamide. Fifteen patients received first BMT for relapsed or refractory
acute myelogenous leukemia or accelerated or blastic
chronic myelogenous leukemia; four received second BMT for relapsed chronic or accelerated
chronic myelogenous leukemia. Doses of 131I-M195 ranged from 120 to 230 mCi/m2. Few toxicities could be attributed to 131I-M195
therapy, and all patients engrafted. Eighteen patients achieved complete remission. Among those patients receiving first BMT, three have remained in unmaintained remission for 18+ to 29+ months. Six patients relapsed, including one with isolated
central nervous system disease 32 months after BMT. Ten patients died
in complete remission of transplant-related complications. Second, we studied whether 131I-M195 could reduce
minimal residual disease and prolong remission and survival durations safely in patients with relapsed
acute promyelocytic leukemia after they attained remission with
all-trans-retinoic acid. Seven patients were treated with either 50 or 70 mCi/m2 131I-M195. Toxicity was limited to myelosuppression. As a measure of
minimal residual disease, we monitored PML/RAR-alpha
mRNA by reverse transcription PCR. Six patients had positive reverse transcription PCR assays prior to receiving 131I-M195; two converted transiently to negative. Median disease-free survival and overall survival of the seven patients were 8 (range, 3-14.5) months and 28 (range, 5.5-43+) months, respectively. This regimen compares favorably with others for relapsed
acute promyelocytic leukemia. In an effort to avoid nonspecific cytotoxicity associated with 131I in future trials for
minimal residual disease, we have conjugated short-range, alpha particle-emitting
radioisotopes to
HuM195 using a bifunctional chelate, 2-(p-isothiocyanatobenzyl)-cyclohexyldiethyl-enetriaminep entaacetic
acid, with high efficiency and specific activities. 212Bi-HuM195 has demonstrated dose- and specific activity-dependent killing of HL60 cells in vitro. Injection of 213Bi-HuM195 into healthy BALB/c mice produced no effects on weight or viability.