ABSTRACT
Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.
Subject(s)
Genetic Therapy/adverse effects , Mutagens/adverse effects , Wiskott-Aldrich Syndrome Protein/genetics , Wiskott-Aldrich Syndrome Protein/therapeutic use , Wiskott-Aldrich Syndrome/therapy , Adolescent , Animals , Blood Platelets/metabolism , Child , Child, Preschool , Clone Cells , Colitis/etiology , Disease Progression , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Lymphocytes/metabolism , Mice , Mice, Inbred NOD , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Thrombocytopenia/therapy , Transplantation, Autologous , Treatment Outcome , Wiskott-Aldrich Syndrome/pathology , Wiskott-Aldrich Syndrome Protein/metabolismABSTRACT
To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 µg/l (95% confidence intervals, -1411, -280 µg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.
Subject(s)
Anemia, Sickle Cell/therapy , Benzoates/therapeutic use , Iron Chelating Agents/therapeutic use , Iron Overload/drug therapy , Transfusion Reaction , Triazoles/therapeutic use , Adolescent , Adult , Aged , Benzoates/administration & dosage , Benzoates/adverse effects , Child , Child, Preschool , Deferasirox , Drug Administration Schedule , Female , Gastrointestinal Diseases/chemically induced , Humans , Iron Chelating Agents/administration & dosage , Iron Chelating Agents/adverse effects , Iron Overload/etiology , Male , Middle Aged , Treatment Outcome , Triazoles/administration & dosage , Triazoles/adverse effects , Young AdultABSTRACT
BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is known for its propensity to metastasize to bone, but it also spreads to other sites including the brain. This study was undertaken to describe the treatment and outcomes of patients with recurrent CCSK involving the brain. METHODS: A retrospective records review was conducted on eight patients with CCSK who developed brain metastases after complete responses to initial therapy. RESULTS: The recurrences occurred at a median of 24.5 months after initial diagnosis (range, 12-53 months). At the time of recurrence, patients were treated with multimodal therapy including biopsy or resection, radiation therapy, and chemotherapy. All patients received a variable number of courses of ifosfamide, carboplatin, and etoposide (ICE), with or without other agents. Four patients received high-dose chemotherapy with autologous stem cell rescue. One patient died from complications of bacteremia 8 weeks after starting chemotherapy. The other seven patients achieved a complete response after either surgery or ICE chemotherapy. Of these, six patients were alive without disease with a median follow-up of 30 months from the time of recurrence (range, 24 to 71 months). All six survivors received radiation therapy and four had gross total resections. Three survivors received high-dose chemotherapy with stem cell rescue. CONCLUSION: Patients with recurrent CCSK involving the brain can have durable survival after recurrence. ICE chemotherapy, together with radiation therapy and surgery, provides a reasonable salvage regimen for recurrent CCSK. It is unclear whether high-dose chemotherapy confers a benefit compared to conventional-dose chemotherapy.