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.
Subject(s)
Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects , Leukemia, Monocytic, Acute/complications , Splenic Rupture/etiology , Antigens, Neoplasm/analysis , Antigens, Surface/analysis , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Marrow/drug effects , Bone Marrow/immunology , Bone Marrow Cells , Cell Adhesion Molecules/physiology , Cytarabine/administration & dosage , Cytarabine/adverse effects , Daunorubicin/administration & dosage , Daunorubicin/adverse effects , Female , Hematopoietic Cell Growth Factors/pharmacology , Hematopoietic Stem Cells/drug effects , Hematopoietic Stem Cells/pathology , Humans , Leukemia, Monocytic, Acute/drug therapy , Leukemia, Monocytic, Acute/immunology , Middle Aged , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Recombinant Proteins/adverse effects , Splenic Rupture/chemically induced , Thioguanine/administration & dosage , Thioguanine/adverse effects , Tumor Cells, Cultured/drug effectsABSTRACT
An 8-month-old male patient with severe combined immunodeficiency syndrome was transplanted with maternal, haploidentical T cell-depleted bone marrow without prior conditioning therapy. Acute graft-versus-host disease developed 2 weeks post bone marrow transplantation (BMT) and was successfully treated with cortisone. After cortisone withdrawal the patient developed myeloid and B cell depression concomitant with T cell activation. For specific T cell modulation, treatment with the T cell receptor (TCR) alpha beta chain-binding MoAb BMA031 was initiated in combination with cyclosporin A. GM-CSF was given to enhance myeloid reconstitution. About 1 year post BMT, B cell and granulocyte counts were within the normal range with stable chimerism in both lineages. B cell proliferation tests were normal and first signs of in vitro immunoglobulin synthesis occurred.
