Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia
Shahrzad Bakhtiar1†, 
Sandra Woelke2†, 
Sabine Huenecke1, 
Matthias Kieslich3, Alexander Malcolm Taylor4, 
Ralf Schubert2, 
Stefan Zielen2 and 
Peter Bader1*- 1Division for Stem Cell Transplantation and Immunology, Children's Hospital, Goethe-Universität Frankfurt am Main, Frankfurt, Germany
- 2Department of Allergology, Pneumology and Cystic Fibrosis, Children's Hospital, Goethe-Universität Frankfurt am Main, Frankfurt, Germany
- 3Department of Neuropaediatrics, Children's Hospital, Goethe-Universität Frankfurt am Main, Frankfurt, Germany
- 4Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
Ataxia telangiectasia (A-T) is a primary immunodeficiency with mutations in the gene encoding the A-T mutated (ATM) protein that interacts with immune, hematopoietic, and endocrine targets resulting in broad multi-systemic clinical manifestations with a devastating outcome. Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies. It is a matter of discussion whether pre-emptive allogeneic hematopoietic stem cell transplantation (alloHSCT) using a reduced intensity conditioning regimen would be an option to restore immune-competence and prevent malignancy, as shown in animal models, because conventional treatment protocols of malignant diseases using radio- and/or chemotherapy have a high rate of therapy-related morbidity and mortality in these patients. We present the course of the disease, including immune reconstitution and neurological outcome following pre-emptive alloHSCT in a 4-year-old boy with A-T on a 6 year follow-up. Our manuscript provides a proof-of-concept of alloHSCT as an individual pre-emptive treatment strategy from which some A-T patients might benefit.
Ataxia telangiectasia (A-T) is a primary immunodeficiency with mutations in the gene encoding the A-T mutated (ATM) protein that interacts with immune, hematopoietic, and endocrine targets resulting in broad multi-systemic clinical manifestations. Beside a progressive neurodegenerative course, A-T leads to significantly increased susceptibility to malignancies which affects 25% of patients at a median age of 12.5 years (1). It is the subject of ongoing studies to determine whether a lack of immunological surveillance is responsible for the increased risk of malignancy, the disturbed cell regulative capacity of the ATM protein, or both. The incidence of cancer does not correlate with the type of ATM mutation, but rather with the extent of immunodeficiency, particularly profound IgA deficiency and a low number of B cells (1).
In our A-T cohort of 70 patients, we observed malignancies in 16 cases who received chemotherapy by protocol or individualized treatment. Other than three patients under current treatment, 12 others died regardless of the treatment intensity (unpublished data). These results emphasize the substantial need for novel preventive and curative treatment options for malignancies in A-T.
Regarding neurological outcome, a phase III trial is ongoing to assess the effects of monthly transfusions of dexamethasone-loaded autologous erythrocytes, following a phase II trial showing improvement of neurological symptoms (2). The extent to which steroid treatment might have an impact on immunodeficiency and susceptibility to malignancies in A-T patients remains to be evaluated.
Allogeneic hematopoietic stem cell transplantation (alloHSCT), as performed for other genetic instability syndromes, is an encouraging approach to correct immunity and prevent the development of hematologic malignancies. However, alloHSCT is not performed routinely in A-T patients due to the toxicity of the conventional conditioning regimen (3). Herein, we present the course of the disease, including immune reconstitution and neurological outcome following pre-emptive alloHSCT, as an individual treatment strategy to restore immunodeficiency and prevent malignancy, in a 4-year-old boy with A-T on a 6 year follow-up.