Fanconi anaemia: new strategies

Abstract

Fanconi anaemia (FA) is a rare genetic disease characterized by chromosomal instability, somatic abnormalities, marrow failure and cancer proness. The main cause of morbidity and mortality is bone marrow failure, which typically arises in the first decade of life and progresses to full-blown transfusion dependence and severe neutropenia in a variable number of years. Myelodysplastic syndrome (MDS) and AML may arise on the background of marrow failure, although cases of patients diagnosed with MDS or overt leukaemia before the full appearance of marrow aplasia are reported. This article reviews the current options for treatment of bone marrow failure in FA and provides an algorithm for supporting decisions on treatment. The use of androgens, corticosteroids and growth factors is reviewed, as well as the results in recent cohorts of matched sibling donor haematopoietic stem cell (HSC) transplants and unrelated donor HSC transplants, including cord blood graft. The conditioning regimens used are analysed and commented. Up-to-date information on second tumours after HSC transplant and on experimental treatments such as gene therapy, prenatal and preimplantation diagnosis and inhibition of proinflammatory cytokines is provided.

Características clínicas de pacientes com anemia de Fanconi

“…Moreover, the diagnosis allows for appropriate treatment of patients because individuals with FA may experience greater toxicity if they receive a standard dose of chemotherapy regimens before transplantation of hematopoietic stem cells (29,30) . Since there is late onset of pancytopenia, the diagnosis of FA should be considered in all children with characteristic dysmorphic findings, even in the absence of hematological abnormalities (6) .…”

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)

“…Time point of eligibility to HSCT was determined retrospectively from the CRF of each patient, considering the date of appearance of moderate or severe cytopenia (as first known consistent blood count or worsening to moderate or severe cytopenia from no or mild cytopenia) or MDS, AML, cytogenetic abnormality. The definition of this time point comes from literature [6,7] and consolidated clinical practice.…”

From the Molecular Biology to the Gene Therapy of a DNA Repair Syndrome: Fanconi Anemia

“…Many of the treatments of the BMF are palliative and directed to maintain acceptable numbers of peripheral blood cells. The use of androgens, in some cases combined with corticoids, constitute one of the most common treatments of FA patients in early stages of the disease, when a residual endogenous hematopoiesis remains [43,77]. However, not all the patients respond to this treatment and, in most cases the response is slow, transient and normally limited to the red blood cells.…”

“…However, not all the patients respond to this treatment and, in most cases the response is slow, transient and normally limited to the red blood cells. Although a longer survival has been reported in patients who have been treated with androgens, in comparison with those who have not (20 years vs 14 years) [77], it has been reported that their use might constitute an adverse predictor when hematopoietic cell transplantation (HCT) is required [78]. Additionally, side effects such as liver tumors [48,79] and masculinization may occur when androgens are used [80].…”

“…In 1984, Gluckman et al [84] developed the first successful conditioning regimen for FA patients consisting of a low dose of cyclophosphamide (CY) and a single dose of total body irradiation (TBI). Since then, many different protocols have been developed aiming to limit the radiation exposure in HCT preparative regimens [85], and thus to minimize risks of malignancies in the long-term [77]. As a result of these improvements, current HCTs from HLA(Human Leukocyte Antigen) identical siblings do not generally include irradiation in the conditioning.…”