Hematopoietic stem cell transplantation in patients with Fanconi anemia for bone marrow failure in the Czech Republic and Slovakia (2005-2016)
Abstract
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 (me-dian 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 multidis-ciplinary 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.