Wagner, JE, Eapen, M, MacMillan, ML, Harris, RE, Pasquini, R, Boulad, F et al.. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 109: 2256-2262

The Rockefeller University, New York, New York, United States
Blood (Impact Factor: 10.45). 04/2007; 109(5):2256-62. DOI: 10.1182/blood-2006-07-036657
Source: PubMed


Bone marrow transplantation (BMT) is the only known cure for the hematologic manifestations of Fanconi anemia (FA). Potential benefits of unrelated donor BMT for FA, however, have been severely limited by graft rejection and treatment-related mortality with resultant poor survival. Therefore, we evaluated the impact of potential prognostic factors on hematopoietic recovery, graft-versus-host disease (GVHD), and mortality in 98 recipients of unrelated donor BMT who received transplants between 1990 and 2003. Probabilities of neutrophil (89% vs 69%; P = .02) and platelet (74% vs 23%; P < .001) recovery were higher after fludarabine-containing regimens than nonfludarabine-containing regimens. Risks of acute GVHD (relative risk [RR], 4.29; P < .001) were higher with non-T-cell-depleted grafts. The day-100 mortality rate was significantly higher after nonfludarabine-containing regimens than fludarabine-containing regimens (65% vs 24%, respectively; P < .001). Corresponding 3-year adjusted overall survival rates were 13% versus 52% (P < .001). In addition, mortality was higher in recipients who were older (> 10 years), who were cytomegalovirus (CMV) seropositive, and who received more than 20 blood product transfusions before BMT. Based on these results, significant practice changes are suggested: use of a fludarabine-containing conditioning regimen in the context of T-cell-depleted marrow allografts, and earlier referral for transplantation prior to excessive transfusions in patients with marrow failure.

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Available from: Arleen D Auerbach, May 30, 2014
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    • "Bone marrow transplantation (BMT) or HSCT is the only curative therapy for marrow failure in FA patients. Early attempts with BMT for the treatment of marrow failure had a limited success as excessive regimenrelated toxicity, graft failure, and severe acute graft-versus-host disease (GVHD) leads to high mortality rate (Davies et al. 1996; Gluckman et al. 1995; Wagner et al. 2003). There is also a risk of developing solid tumours at later stages after the hematopoietic stem cell transplantation . "
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    ABSTRACT: Fanconi Anemia (FA) is a rare disorder with incidence of 1in 350,000 births. It is characterized by progressive bone marrow failure leading to death of many patients in their childhood while development of cancer at later stages of life in some. The treatment of FA is still a medical challenge. Current treatments of FA include androgen administration, hematopoietic growth factors administration and hematopoietic stem cell transplantation (HSCT). Clinical gene therapy trials are still ongoing. The partial success of current therapies has renewed interest in the search for new treatments. Generation of patient-specific induced pluripotent stem (iPS) has shown promising results for cell and gene based therapy. Small molecule interventions have been observed to delay tumor onset in FA. Tumors deficient in FA pathway can be treated by profiling of DNA repair pathway through synthetic lethality mechanism. Targeting toll-like receptor 8 (TLR8) dependent TNFα overexpression is yet another upcoming therapeutic approach to treat FA patients. In conclusion, in the present scenario of treatments available for FA, a proper algorithm of treatment decisions must be followed for better management of FA patients and to ensure their increased survival. Innovative therapeutic approaches that can prevent both anemia and cancer should be developed for more effective treatment of FA.
    Full-text · Article · Dec 2012 · HUGO Journal
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    • "However, with the advent of fludarabine-based conditioning regimens there has been a notable improvement. Fludarabine-based conditioning regimens are associated with a superior engraftment and better OS (3-year adjusted OS rates were 52% with fludarabine versus 13% without fludarabine P < 0·001; Wagner et al, 2007). Cord stem cells are an attractive option for patients lacking a MUD. "
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    ABSTRACT: Aplastic anaemia (AA) is a rare heterogeneous condition in children. 15-20% of cases are constitutional and correct diagnosis of these inherited causes of AA is important for appropriate management. For idiopathic severe aplastic anaemia, a matched sibling donor (MSD) haematopoietic stem cell transplant (HSCT) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. IST with horse anti-thymocyte globulin (ATG) is superior to rabbit ATG and has good long-term results. In contrast, IST with rabbit ATG has an overall response of only 30-40%. Due to improvements in outcome over the last two decades in matched unrelated donor (MUD) HSCT, results are now similar to that of MSD HSCT. The decision to proceed with IST with ATG or MUD HSCT will depend on the likelihood of finding a MUD and the differing risks and benefits that each therapy provides.
    Preview · Article · Feb 2012 · British Journal of Haematology
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    • "More than 90% of FA patients develop marrow failure during life with a median onset at approximately 8 years of age [1]. Although the outcome of allogeneic stem cell transplantation of FA patients with matched related and unrelated stem cell donors has dramatically improved over the last 10 years, a significant number of patients still die during this treatment or experience the early development of secondary malignancies as consequence of the genotoxic conditioning regimens in combination with the occurrence of acute or chronic graft-versus-host disease (GvHD) [5] [6] [7] [8]. Over the last 50 years, several synthetic androgens have been established as an alternative treatment option for different forms of aplastic anemia [9]. "
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    ABSTRACT: More than 90% of Fanconi anemia (FA) patients experience progressive bone marrow failure during life with a median onset at 8 years of age. As matched sibling donor transplantation as preferred treatment is not available for the majority of patients, several synthetic androgens have been used as short-term treatment options for the marrow failure in FA patients for more than 50 years. Here, we retrospectively collected data on eight FA patients who received danazol for the off-label treatment of their marrow failure at a starting dose of approximately 5mg/kg body weight/die. The hematological parameters at the initiation of treatment were hemoglobin (Hb) <8 g/dL and/or thrombocytes <30,000/μl. In 7 out of 8 FA patients, the values for both parameters rose on average >50% over the starting counts within 6 months and remained stable for up to 3 years despite careful reduction of the danazol dose per kg body weight. In 4 patients with a follow-up of 3 years, the platelets finally reached an average of 68,000/μL or 2.8 times over the starting values, while the Hb remained stable >11 g/dL. Danazol was reduced to 54% of the starting dose or 2.6 mg/kg/die. One FA-A patient with an unusually severe phenotype did not response with her PB counts to either danazol or oxymethalone within 6 months. None of the patients developed severe or unacceptable side-effects from the danazol treatment that led to the discontinuation of therapy. This initial description suggests that danazol might be an effective and well-tolerated treatment option for delaying the progressive marrow failure in FA patients for at least 3 years and longer.
    Full-text · Article · Dec 2011 · Blood Cells Molecules and Diseases
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