title: Sequential targeted therapy for relapsed acute promyelocytic leukemia with all-trans retinoic acid and anti-CD33 monoclonal antibody M195.
abstract: Acute promyelocytic leukemia (APL) provides a model to examine the sequential use of selective oncogene product-targeted and lineage-targeted 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 and reduce large leukemic burdens when labeled with 131I. We studied whether 131I-M195 could safely reduce minimal residual disease and prolong remission and survival durations in patients with relapsed APL after they had attained remission with all-trans RA. Seven patients with relapsed APL in second remission were treated with either 70 (n = 2) or 50 (n = 5) mCi/m2 of 131I-M195. As a measure of minimal residual disease, we serially monitored PML/RAR-alpha mRNA by a reverse transcription polymerase chain reaction (RT-PCR) assay. There was no immediate toxicity. Late toxicity was limited to myelosuppression, but no episodes 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 131I-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 survival exceeds 21+ months (range 5.5-33+). This regimen based on targeted therapy compares favorably to other approaches for the treatment of relapsed APL, including that used in the immediately preceding trial in which patients were induced into remission and maintained with all-trans RA, as well as other chemotherapy-based regimens. These data support further study of moAb-based therapy for minimal residual disease in acute leukemia.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: J G
authors.initials: JG
authors.lastname: Jurcic
authors.forename: P C
authors.initials: PC
authors.lastname: Caron
authors.forename: W H
authors.initials: WH
authors.lastname: Miller
authors.forename: T J
authors.initials: TJ
authors.lastname: Yao
authors.forename: P
authors.initials: P
authors.lastname: Maslak
authors.forename: R D
authors.initials: RD
authors.lastname: Finn
authors.forename: S M
authors.initials: SM
authors.lastname: Larson
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
authors.forename: D A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D002454:Cell Differentiation / Q000187:drug effects; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage; D007155:Immunologic Factors / Q000627:therapeutic use*; D015473:Leukemia, Promyelocytic, Acute / Q000401:mortality / Q000628:therapy*; D015993:Life Tables; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins; D018365:Neoplasm, Residual; D009503:Neutropenia / Q000209:etiology; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000032:analysis; D016133:Polymerase Chain Reaction; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid / Q000032:analysis; D012074:Remission Induction; D016879:Salvage Therapy; D063268:Sialic Acid Binding Ig-like Lectin 3; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis; D016896:Treatment Outcome; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D025521:Tumor Suppressor Proteins
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D007155:Immunologic Factors; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D018168:Receptors, Retinoic Acid; D063268:Sialic Acid Binding Ig-like Lectin 3; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D003561:Cytarabine; C070576:PML protein, human; D014212:Tretinoin; D015255:Idarubicin; D003630:Daunorubicin