From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
l l l TRANSPLANTATION
Comment on MacMillan et al, page 3798
Improving survival for Fanconi anemia patients ----------------------------------------------------------------------------------------------------Eliane Gluckman
HOSPITAL SAINT LOUIS, UNIVERSITY PARIS-DIDEROT
In this issue of Blood, MacMillan et al give the results of sequential modifications of the conditioning regimen to improve the outcome of unrelated bone marrow transplantation in Fanconi anemia (FA). Over a period of 10 years, they show that transplant toxicity has decreased and engraftment has improved, resulting in a 5-year overall survival probability of 94%. The major change was the use of fludarabine in the conditioning, with decreased doses of irradiation and cyclophosphamide. They attribute their success to progressive modifications of the conditioning regimen; nevertheless, the improvement may also have been due to better patient selection, use of high-resolution HLA typing for donor selection, and improved supportive care treatment.1
F
A is a rare genetic disease characterized by progressive bone marrow failure, malformations, and a high propensity of malignancies, including acute myeloid leukemia/myelodysplastic syndrome and squamous cell carcinomas. FA is caused by biallelic mutations in 1 of the 17 gene mutations (called FA complementation groups A through Q) involved in DNA repair processes known as the FA pathway. The underlying cause is genomic instability resulting from the deficiency in the replicationdependent DNA cross-link repair pathway commonly referred to as the FA/BRCA pathway.2 The prognosis of FA patients is poor, most dying before the age of 10 years from severe aplastic anemia. The only known curative treatment is hematopoietic stem cell transplant. Historically, it was recognized that the combination of alkylating agents and irradiation previously used for conditioning for acquired aplastic anemia led to unacceptable toxicity in FA patients. In vitro testing of FA cells with an alkylating agent such as cyclophosphamide, diepoxybutane, or mitomycin C showed increased chromosome breaks, which became the basis for FA diagnosis.3 Following this observation, the conditioning protocol was modified by reducing the doses of cyclophosphamide and irradiation, resulting in a dramatic
3676
improvement in survival.4,5 Several complications remained, including increased incidence and severity of acute and chronic graft-versus-host disease6 and, long-term, a high incidence of head and neck carcinomas.7 Because of these short- and long-term complications, the use of matched unrelated donors led to higher mortality compared with HLA-identical sibling transplants.8 Unfortunately, there is still a high proportion of patients who do not have a suitable HLA-matched related or unrelated bone marrow donor. HLA-mismatched transplants are currently being investigated. Unrelated HLA-mismatched cord blood transplant has proved its efficacy to treat a high number of patients with malignant or nonmalignant hematologic disorders. A preliminary analysis published in 2007 in patients with FA showed disappointing results, with an overall survival rate of 40%.9 Since that publication in 2007, donor selection has been changed. Now, it is recommended to select units with low-resolution HLA-matched (6/6) or only 1 antigen mismatched (5/6) and .5 3 107 total nucleated cells per kilogram of cord blood for transplant in nonmalignant diseases. Further, new methods of ex vivo expansion of cord blood CD34 cells have dramatically increased the engraftment probability. More recently,
results of related HLA-haploidentical T cell–depleted transplant has been reported in a single-center study, with a 5-year survival rate of 83%.10 Despite this encouraging result of haplotransplant, long-term followup and well-designed prospective studies are needed. With increasing experience over the years, results of hematopoietic stem cell transplant have improved for FA patients. The major challenge is the prevention of late complications, including head and neck carcinoma. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. MacMillan ML, DeFor TE, Young J-AH, et al. Alternative donor hematopoietic cell transplantation for Fanconi anemia. Blood. 2015;125(24):3798-3804. 2. Wang AT, Smogorzewska A. SnapShot: Fanconi anemia and associated proteins. Cell. 2015;160(1-2): 354, e1. 3. Berger R, Bernheim A, Gluckman E, Gisselbrecht C. In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients. Br J Haematol. 1980;45(4):565-568. 4. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation. Br J Haematol. 1983; 54(3):431-440. 5. Gluckman E, Auerbach AD, Horowitz MM, et al. Bone marrow transplantation for Fanconi anemia. Blood. 1995; 86(7):2856-2862. 6. Guardiola P, Soci´e G, Li X, et al. Acute graftversus-host disease in patients with Fanconi anemia or acquired aplastic anemia undergoing bone marrow transplantation from HLA-identical sibling donors: risk factors and influence on outcome. Blood. 2004;103(1): 73-77. 7. Deeg HJ, Soci´e G, Schoch G, et al. Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood. 1996;87(1):386-392. 8. Peffault de Latour R, Porcher R, Dalle JH, et al; FA Committee of the Severe Aplastic Anemia Working Party; Pediatric Working Party of the European Group for Blood and Marrow Transplantation. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. Blood. 2013;122(26): 4279-4286. 9. Gluckman E, Rocha V, Ionescu I, et al; Eurocord-Netcord and EBMT. Results of unrelated cord blood transplant in Fanconi anemia patients: risk factor analysis for engraftment and survival. Biol Blood Marrow Transplant. 2007;13(9): 1073-1082. 10. Zecca M, Strocchio L, Pagliara D, et al. HLAhaploidentical T cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia. Biol Blood Marrow Transplant. 2014;20(4):571-576. © 2015 by The American Society of Hematology
BLOOD, 11 JUNE 2015 x VOLUME 125, NUMBER 24
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 3676 doi:10.1182/blood-2015-04-639476
Improving survival for Fanconi anemia patients Eliane Gluckman
Updated information and services can be found at: http://www.bloodjournal.org/content/125/24/3676.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
l l l TRANSPLANTATION
Comment on MacMillan et al, page 3798
Improving survival for Fanconi anemia patients ----------------------------------------------------------------------------------------------------Eliane Gluckman
HOSPITAL SAINT LOUIS, UNIVERSITY PARIS-DIDEROT
In this issue of Blood, MacMillan et al give the results of sequential modifications of the conditioning regimen to improve the outcome of unrelated bone marrow transplantation in Fanconi anemia (FA). Over a period of 10 years, they show that transplant toxicity has decreased and engraftment has improved, resulting in a 5-year overall survival probability of 94%. The major change was the use of fludarabine in the conditioning, with decreased doses of irradiation and cyclophosphamide. They attribute their success to progressive modifications of the conditioning regimen; nevertheless, the improvement may also have been due to better patient selection, use of high-resolution HLA typing for donor selection, and improved supportive care treatment.1
F
A is a rare genetic disease characterized by progressive bone marrow failure, malformations, and a high propensity of malignancies, including acute myeloid leukemia/myelodysplastic syndrome and squamous cell carcinomas. FA is caused by biallelic mutations in 1 of the 17 gene mutations (called FA complementation groups A through Q) involved in DNA repair processes known as the FA pathway. The underlying cause is genomic instability resulting from the deficiency in the replicationdependent DNA cross-link repair pathway commonly referred to as the FA/BRCA pathway.2 The prognosis of FA patients is poor, most dying before the age of 10 years from severe aplastic anemia. The only known curative treatment is hematopoietic stem cell transplant. Historically, it was recognized that the combination of alkylating agents and irradiation previously used for conditioning for acquired aplastic anemia led to unacceptable toxicity in FA patients. In vitro testing of FA cells with an alkylating agent such as cyclophosphamide, diepoxybutane, or mitomycin C showed increased chromosome breaks, which became the basis for FA diagnosis.3 Following this observation, the conditioning protocol was modified by reducing the doses of cyclophosphamide and irradiation, resulting in a dramatic
3676
improvement in survival.4,5 Several complications remained, including increased incidence and severity of acute and chronic graft-versus-host disease6 and, long-term, a high incidence of head and neck carcinomas.7 Because of these short- and long-term complications, the use of matched unrelated donors led to higher mortality compared with HLA-identical sibling transplants.8 Unfortunately, there is still a high proportion of patients who do not have a suitable HLA-matched related or unrelated bone marrow donor. HLA-mismatched transplants are currently being investigated. Unrelated HLA-mismatched cord blood transplant has proved its efficacy to treat a high number of patients with malignant or nonmalignant hematologic disorders. A preliminary analysis published in 2007 in patients with FA showed disappointing results, with an overall survival rate of 40%.9 Since that publication in 2007, donor selection has been changed. Now, it is recommended to select units with low-resolution HLA-matched (6/6) or only 1 antigen mismatched (5/6) and .5 3 107 total nucleated cells per kilogram of cord blood for transplant in nonmalignant diseases. Further, new methods of ex vivo expansion of cord blood CD34 cells have dramatically increased the engraftment probability. More recently,
results of related HLA-haploidentical T cell–depleted transplant has been reported in a single-center study, with a 5-year survival rate of 83%.10 Despite this encouraging result of haplotransplant, long-term followup and well-designed prospective studies are needed. With increasing experience over the years, results of hematopoietic stem cell transplant have improved for FA patients. The major challenge is the prevention of late complications, including head and neck carcinoma. Conflict-of-interest disclosure: The author declares no competing financial interests. n REFERENCES 1. MacMillan ML, DeFor TE, Young J-AH, et al. Alternative donor hematopoietic cell transplantation for Fanconi anemia. Blood. 2015;125(24):3798-3804. 2. Wang AT, Smogorzewska A. SnapShot: Fanconi anemia and associated proteins. Cell. 2015;160(1-2): 354, e1. 3. Berger R, Bernheim A, Gluckman E, Gisselbrecht C. In vitro effect of cyclophosphamide metabolites on chromosomes of Fanconi anaemia patients. Br J Haematol. 1980;45(4):565-568. 4. Gluckman E, Devergie A, Dutreix J. Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation. Br J Haematol. 1983; 54(3):431-440. 5. Gluckman E, Auerbach AD, Horowitz MM, et al. Bone marrow transplantation for Fanconi anemia. Blood. 1995; 86(7):2856-2862. 6. Guardiola P, Soci´e G, Li X, et al. Acute graftversus-host disease in patients with Fanconi anemia or acquired aplastic anemia undergoing bone marrow transplantation from HLA-identical sibling donors: risk factors and influence on outcome. Blood. 2004;103(1): 73-77. 7. Deeg HJ, Soci´e G, Schoch G, et al. Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood. 1996;87(1):386-392. 8. Peffault de Latour R, Porcher R, Dalle JH, et al; FA Committee of the Severe Aplastic Anemia Working Party; Pediatric Working Party of the European Group for Blood and Marrow Transplantation. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. Blood. 2013;122(26): 4279-4286. 9. Gluckman E, Rocha V, Ionescu I, et al; Eurocord-Netcord and EBMT. Results of unrelated cord blood transplant in Fanconi anemia patients: risk factor analysis for engraftment and survival. Biol Blood Marrow Transplant. 2007;13(9): 1073-1082. 10. Zecca M, Strocchio L, Pagliara D, et al. HLAhaploidentical T cell-depleted allogeneic hematopoietic stem cell transplantation in children with Fanconi anemia. Biol Blood Marrow Transplant. 2014;20(4):571-576. © 2015 by The American Society of Hematology
BLOOD, 11 JUNE 2015 x VOLUME 125, NUMBER 24
From www.bloodjournal.org by guest on September 11, 2016. For personal use only.
2015 125: 3676 doi:10.1182/blood-2015-04-639476
Improving survival for Fanconi anemia patients Eliane Gluckman
Updated information and services can be found at: http://www.bloodjournal.org/content/125/24/3676.full.html Articles on similar topics can be found in the following Blood collections Free Research Articles (4041 articles) Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
