#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Hematopoietic stem cell transplantation in patients with Fanconi anemia for bone marrow failure in the Czech Republic and Slovakia (2005–2016)


Authors: P. Sedláček 1;  P. Švec 2;  S. Tavandzis 3;  P. Keslová 1;  R. Formánková 1;  I. Boďová 2;  P. Říha 1;  S. Šufliarska 2;  M. Vraná 4;  J. Starý 1;  J. Horáková 2
Authors place of work: Klinika dětské hematologie a onkologie 2. LF UK a FN Motol, Praha 1;  Klinika detskej hematológie a onkologie, Národný ústav detských chorôb, Bratislava, Slovensko 2;  Laboratoř molekulární biologie, Laboratoře Agel, Nový Jičín 3;  Národní referenční laboratoř pro DNA diagnostiku, HLA laboratoř, Ústav hematologie a krevní transfuze, Praha 4
Published in the journal: Čes-slov Pediat 2020; 75 (7): 427-435.
Category: Original Papers

Summary

Objective: The aim of the study was to evaluate the current approach to pediatric patients with Fanconi anemia and bone marrow failure from the perspective of the indication for hematopoietic stem cell transplantation. Fanconi anemia (FA) is a rare genetically and clinically heterogeneous syndrome with a significantly increased predisposition to developing bone marrow failure or malignancy (leukemia, solid tumors). FA is characterized by the presence of somatic anomalies occurring in approximately 75–80% of affected individuals which include one or more of the following conditions: small stature, abnormal skin pigmentation, upper or lower limb skeletal malformation, microcephaly and visual and urogenital anomaly. The cumulative risk of developing bone marrow failure is 50%. Progressive bone marrow failure typically occurs in the first decade of age, often initially with thrombocytopenia or leukopenia. Leukemia and carcinomas occur as early as in 16 years of age. Diagnosis of FA is based on functional test of increased chromosome fragility without or with stimulation of lymphocytes with diepoxybutane (DEB) or mitomycin C (MMC). The diagnosis is confirmed by detection of a mutation in one of the genes of the Fanconi complex.

Methods: Our cohort includes 13 children (7 boys and 6 girls) diagnosed with FA aged 0–11.4 years (median 5.8) between 2005 and 2016. The first symptoms were the presence of obvious congenital anomalies (n=4) or cytopenia (n=9). Genetic examination confirmed gene mutations in FANCA group in eight, FANCG in three, FANCD2 in one, in one retrospective examination is pending. Indication for hematopoietic stem cell transplantation (HSCT) was bone marrow failure diagnosed at a median age of 6.4 years (3.2–11.4). HSCT was performed at the age of 4.6–15.1 years (median 8.3). The stem cell source was bone marrow (n=8), peripheral stem cells (n=3) or cord blood (n=2) of an HLA identical unrelated donor (n=11) or a healthy HLA identical sibling (n=2).

Results: All patients achieved stable hematopoietic engraftment after HSCT. Inadequate immune reconstitution was a contributing cause of death in two patients who died of CMV pneumonia 2.5 and 13 months after transplantation. In the other two patients we have diagnosed cancer 7 and 10 years after transplantation (both aged 15 years). The age of eleven living patients at the time of the last follow-up is 12.1–24.4 years (median 19.4). A total of 11/13 patients (OS 84.6%) are alive in the median follow-up 
10 years (now 4.8–15.2 years) after transplantation.

Conclusions: HSCT is a demanding medical procedure in patients with FA. Taking into account the biology of the disease for choice of the conditioning regimen and concentration of the patients in centers with a great transplantation experience, it achieves very good results. It is an effective therapy of bone marrow failure and prevents further development of hematological malignancies. However, the indication needs to be considered very carefully, because HSCT is a significant burden on the body and it is speculated that its implementation may impact on increased risk of developing non-haematological malignancies. However, HSCT results in significant prolongation of life in well-indicated patients. A lifelong multidisciplinary follow-up of all patients with FA is essential for early detection of bone marrow failure or any malignant disease. Preventive measures include minimizing radiation exposure and contact with harmful substances (including smoking). Vaccination against human papillomavirus (HPV) is recommended to reduce the risk of gynecological cancer in women and oral cancer in all subjects.

Keywords:

hematopoietic stem cell transplant – Fanconi anemia – bone marrow failure – carcinoma – dispensary care


Zdroje

1. Alter BP, Giri N, Savage SA, et al. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica 2018; 103 (1): 30–39.

2. Dietz AC, Duncan CN, Alter BP, et al. The Second Pediatric Blood and Marrow Transplant Consortium International Consensus Conference on Late Effects after Pediatric Hematopoietic Cell Transplantation: Defining the unique late effects of children undergoing hematopoietic cell transplantation for immune deficiencies, inherited marrow failure disorders, and hemoglobinopathies. Biol Blood Marrow Transplant 2017; 23 (1): 24–29.

3. Pospisilova D. Current perspectives on inherited bone marrow syndromes. Čes-slov Pediat 2016; 71 (4): 216–228.

4. Fiesco-Roa MO, Giri N, McReynolds LJ, et al. Genotype-phenotype associations in Fanconi anemia: A literature review. Blood Rev 2019; 37: 100589.

5. Tsui V, Crismani W. The Fanconi anemia pathway and fertility. Trends Genet 2019; 35 (3): 199–214.

6. Soulier J, Leblanc T, Larghero J, et al. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA//BRCA pathway. Blood 2005; 105 (3): 1329–1336.

7. Nicoletti E, Rao G, Bueren JA, et al. Mosaicism in Fanconi anemia: concise review and evaluation of published cases with focus on clinical course of blood count normalization. Ann Hematol 2020. Epub 2020/02/18. doi: 10.1007/s00277-020-03954-2.

8. Gennery AR, Slatter MA, Bhattacharya A, et al. The clinical and biological overlap between Nijmegen Breakage syndrome and Fanconi anemia. Clin Immunol 2004; 113 (2): 214–219.

9. Bogliolo M, Pujol R, Aza-Carmona M, et al. Optimised molecular genetic diagnostics of Fanconi anaemia by whole exome sequencing and functional studies. J Med Genet 2020; 57 (4): 258268.

10. Alter BP. Fanconi anemia in blacks. Am J Med Genet 1992; 42 (3): 393–394.

11. Kutler DI, Auerbach AD. Fanconi anemia in Ashkenazi Jews. Fam Cancer 2004; 3 (3–4): 241–248.

12. Svahn J, Bagnasco F, Cappelli E, et al. Somatic, hematologic phenotype, long-term outcome, and effect of hematopoietic stem cell transplantation. An analysis of 97 Fanconi anemia patients from the Italian national database on behalf of the Marrow Failure Study Group of the AIEOP (Italian Association of Pediatric Hematology-Oncology). Am J Hematol 2016; 91 (7): 666–671.

13. Ebens CL, DeFor TE, Tryon R, et al. Comparable outcomes after HLA-matched sibling and alternative donor hematopoietic cell transplantation for children with Fanconi anemia and severe aplastic anemia. Biol Blood Marrow Transplant 2018; 24 (4): 765–771.

14. Chao MM, Ebell W, Bader P, et al. Consensus of German transplant centers on hematopoietic stem cell transplantation in Fanconi anemia. Klin Padiatr 2015; 227 (3): 157165.

15. Chao MM, Kuehl JS, Strauss G, et al. Outcomes of mismatched and unrelated donor hematopoietic stem cell transplantation in Fanconi anemia conditioned with chemotherapy only. Ann Hematol 2015; 94 (8): 1311–1318.

16. Paustian L, Chao MM, Hanenberg H, et al. Androgen therapy in Fanconi anemia: A retrospective analysis of 30 years in Germany. Pediatr Hematol Oncol 2016; 33 (1): 5–12.

17. Kutler DI, Auerbach AD, Satagopan J, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg 2003; 129 (1): 106–112.

18. Garcia MJ, Fernandez V, Osorio A, et al. Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition. Carcinogenesis 2009; 30 (11): 1898–1902.

19. Puchmajerova A, Svojgr K, Novotna D, et al. Fanconi anemia, complementation group D1 caused by biallelic mutations of BRCA2 gene – case report. Klin Onkol 2016; 29 (Suppl 1): S89–S92.

20. Alter BP, Rosenberg PS, Brody LC. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 2007; 44 (1): 1–9.

21. Guardiola P, Pasquini R, Dokal I, et al. Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation. Blood 2000; 95 (2): 422–429.

22. Wagner JE, Eapen M, MacMillan ML, et al. Unrelated donor bone marrow transplantation for the treatment of Fanconi anemia. Blood 2007; 109 (5): 2256–2262.

23. Peffault de Latour R, Porcher R, Dalle JH, et al. Allogeneic hematopoietic stem cell transplantation in Fanconi anemia: the European Group for Blood and Marrow Transplantation experience. Blood 2013; 122 (26): 4279–4286.

24. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi‘s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989; 321 (17): 1174–1178.

25. MacMillan ML, DeFor TE, Young JA, et al. Alternative donor hematopoietic cell transplantation for Fanconi anemia. Blood 2015; 125 (24): 3798–3804.

26. Kelaidi C, Makis A, Petrikkos L, et al. Bone marrow failure in Fanconi anemia: Clinical and genetic spectrum in a cohort of 20 pediatric pa-tients. J Pediatr Hematol Oncol 2019; 41 (8): 612–617.

27. Pagliuca S, Ruggeri A, Peffault de Latour R. Cord blood transplantation for bone marrow failure syndromes: state of art. Stem Cell Investig 2019; 6: 39.

28. Gluckman E, Rocha V, Ionescu I, et al. 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.

29. Bonfim C, Ribeiro L, Nichele S, et al. Haploidentical bone marrow transplantation with post-transplant cyclophosphamide for children and adolescents with Fanconi anemia. Biol Blood Marrow Transplant 2017; 23 (2): 310–317.

30. Mehta PA, Davies SM, Leemhuis T, et al. Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study. Blood 2017; 129 (16): 2308–2315.

31. Bonfim C, Ribeiro L, Nichele S, et al. Long-term survival, organ function, and malignancy after hematopoietic stem cell transplantation for Fanconi anemia. Biol Blood Marrow Transplant 2016; 22 (7): 1257–1263.

32. Risitano AM, Marotta S, Calzone R, et al. Twenty years of the Italian Fanconi Anemia Registry: where we stand and what remains to be learned. Haematologica 2016; 101 (3): 319–327.

33. Kutler DI, Wreesmann VB, Goberdhan A, et al. Human papillomavirus DNA and p53 polymorphisms in squamous cell carcinomas from Fanconi anemia patients. J Natl Cancer Inst 2003; 95 (22): 1718–1721.

34. Dietz AC, Savage SA, Vlachos A, et al. Late effects screening guidelines after hematopoietic cell transplantation for inherited bone marrow failure syndromes: Consensus statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT. Biol Blood Marrow Transplant 2017; 23 (9): 1422–1428.

Štítky
Neonatology Paediatrics General practitioner for children and adolescents
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#