title: Fatal spleen rupture during induction chemotherapy with rh GM-CSF priming for acute monocytic leukemia. Clinical case report and in vitro studies.
abstract: Recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-SCF) is currently being tested in clinical trials for the treatment of acute myeloid leukemias with two main intentions: reduction of neutropenia and recruitment of leukemic blasts into cell cycle to enhance cytarabine (ara-C) mediated cytotoxicity. We report a case of a fatal spleen rupture in a patient with acute monocytic leukemia (AML M5b) who was treated according to a clinical phase I/II protocol with rh GM-CSF priming and standard induction chemotherapy TAD 9 (thioguanine/ara-C/daunorubicin). During treatment we observed rapidly rising peripheral blast counts and the development of an acute abdomen. Ultrasound examination revealed splenomegaly due to diffuse cellular infiltration and spleen rupture. The patient died 17 days later due to pneumonia and renewed spleen hemorrhage. Bone marrow progenitor assays before treatment showed exclusive growth of monocytoid blast cell colonies (CFU-L). Colony growth could be stimulated with rh GM-CSF and blocked dose-dependently by a monoclonal anti-GM-CSF antibody. CFU-L proliferation also increased after stimulation with rh interleukin-3 (rh IL-3) and supra-additively with rh granulocyte colony-stimulating factor (rh G-CSF) combined with rh GM-CSF. Furthermore, rh GM-CSF induced surface marker expression of CDw 65 and CD 11b on isolated CFU-L blasts. After short-term suspension culture, rh GM-CSF enhanced the expression of CD 29- and CD 11b-adhesion molecules on peripheral blast cells. In summary, this case represents a fatal spleen rupture occurring during rh GM-CSF priming and induction chemotherapy for acute monocytic leukemia. Although the etiology of this spleen rupture remains uncertain, in view of our data we suggest special caution, when further testing this therapy protocol in acute leukemias with monocytic subtype and high peripheral blast cell counts.
authors.affiliation: Department of Hematology and Oncology, Universitätsklinikum Steglitz, Freie Universität Berlin, F.R.G.
authors.forename: B M
authors.initials: BM
authors.lastname: Zimmer
authors.forename: W E
authors.initials: WE
authors.lastname: Berdel
authors.forename: W D
authors.initials: WD
authors.lastname: Ludwig
authors.forename: M
authors.initials: M
authors.lastname: Notter
authors.forename: B
authors.initials: B
authors.lastname: Reufi
authors.forename: E
authors.initials: E
authors.lastname: Thiel
mesh_terms: D000951:Antigens, Neoplasm / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells; D015815:Cell Adhesion Molecules / Q000502:physiology; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007948:Leukemia, Monocytic, Acute / Q000150:complications* / Q000188:drug therapy / Q000276:immunology; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D011994:Recombinant Proteins / Q000009:adverse effects; D013161:Splenic Rupture / Q000139:chemically induced / Q000209:etiology*; D013866:Thioguanine / Q000008:administration & dosage / Q000009:adverse effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D015815:Cell Adhesion Molecules; D016298:Hematopoietic Cell Growth Factors; D011994:Recombinant Proteins; D003561:Cytarabine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013866:Thioguanine; D003630:Daunorubicin