SEQUENTIAL TARGETED THERAPY FOR RELAPSED ACUTE PROMYELOCYTIC LEUKEMIAWITH ALL-TRANS-RETINOIC ACID AND ANTI-CD33 MONOCLONAL-ANTIBODY M195

Acute promyelocytic leukemia (APL) provides a model to examine the seq uential use of selective oncogene product-targeted and lineage-targete d agents. All-trans retinoic acid (RA) has been shown to produce brief remissions by a novel differentiating mechanism in most patients with APL. M195, a mouse monoclonal antibody (moAb) reactive with the cell- surface antigen CD33, can target myeloid leukemia cells in patients an d reduce large leukemic burdens when labeled with I-131. We studied wh ether I-131-M195 could safely reduce minimal residual disease and prol ong remission and survival durations in patients with relapsed APL aft er they had attained remission with all-trans RA. Seven patients with relapsed APL in second remission were treated with either 70 (n = 2) o r 50 (n = 5) mCi/m(2) of I-131-M195. As a measure of minimal residual disease, we serially monitored PML/RAR-alpha mRNA by a reverse transcr iption polymerase chain reaction (RT-PCR) assay. There was no immediat e toxicity. Late toxicity was limited to myelosuppression, but no epis odes of febrile neutropenia were seen. Six patients had detectable PML /RAR-alpha mRNA after all-trans RA therapy; two had single negative RT -PCR determinations following I-131-M195. Median disease-free survival of the seven patients was 8 months (range 3-14.5). Four patients with median follow-up of 24 months remain alive, and median overall surviv al exceeds 21+ months (range 5.5-33+). This regimen based on targeted therapy compares favorably to other approaches for the treatment of re lapsed APL, including that used in the immediately preceding trial in which patients were induced into remission and maintained with all-tra ns RA, as well as other chemotherapy-based regimens. These data suppor t further study of moAb-based therapy for minimal residual disease in acute leukemia.