The underlying genomic instability that characterizes FA cells promotes the evolution of abnormal hematopoietic cell clones; this, in time, may lead to the development of clonal cytogenetic abnormalities, MDS, and acute leukemia. The most frequently reported chromosomal abnormalities involve gains or deletions of 1q, 3q, 5q, or monosomy 7. Additional complex and noncomplex abnormalities have been reported.7,14,14
The biologic significance of the cytogenetic abnormalities has been unclear because of reports of cytogenetic fluctuation.7,35,35
In patients without FA, MDS is a substantially heterogeneous disease, clinically and biologically, and it mostly affects older individuals,36,37
whereas in patients with FA, MDS and AML occur with the highest frequency during adolescence.3
However, diagnosing MDS in the bone marrow of patients with FA can be particularly challenging, because patients with FA may have dysplastic bone marrow morphology, which may be confused with MDS, and thus, the lack of central review is considered a major limitation in this multicenter study. Furthermore, the relationship between morphologic MDS and clonal cytogenetics is not well defined, although there is evidence that the development of cytogenetic aberrations is an adverse prognostic factor and may predict MDS/AML development and that some cytogenetic aberrations are more deleterious than others. Tonnies et al12
reported that in a cohort of 25 patients with FA, those with 3q aberrations (18 patients) had an increased risk of MDS and AML development compared with those without the aberrations. Mehta et al15
also reported that chromosome 3 and 7 aberrations, but not gain of 1q alone, were associated with increased risk of developing MDS/AML. However, patients with FA with evidence of MDS are more likely to have cytogenetic abnormalities. In a cohort of 23 patients with FA and MDS, 20 had concomitant cytogenetic abnormalities, and on follow-up, no patients demonstrated loss of any clones identified at initial presentation.14
Allogeneic HCT is the only curative modality for the bone marrow manifestations in patients with FA. HLA-matched related donor transplantations have been associated with an excellent outcome, with long-term overall survival of 80% to 85% in some studies.16,18,38–42
) The outcomes of alternative donor transplantations have been less satisfactory, but the results have improved in recent years. The use of fludarabine-based protocols seems to have dramatically increased overall survival and lowered graft rejection rates.16,18,42–44
Allogeneic HCT is also considered the only curative modality for MDS in patients without FA, but because MDS most commonly affects older individuals, the transplantation decision and outcome are influenced by the comorbid medical problems of the patients.45–47
Furthermore, there are currently multiple novel agents offering significant palliation for MDS in patients without FA who are not HCT candidates.48–50
Data on post-HCT outcomes for patients with FA with pretransplantation cytogenetic abnormalities, MDS, or acute leukemia are limited. Most investigators include these patients in HCT studies of the general FA population. Furthermore, the follow-up period for most studies is short. Available data, however, do suggest favorable outcome. Socié et al20
reported five patients with FA and MDS (two also had abnormal cytogenetics) who were conditioned with cyclophosphamide (CY) and thoracoabdominal irradiation, four of whom are alive at 8 years. Ayas et al21
reported on 11 such patients (two with MDS with no cytogenetic abnormalities, eight with MDS and cytogenetic abnormalities, and one with AML with monosomy 7); 10 of 11 patients were alive without disease progression at a median follow-up of 46 months after HCT after conditioning with CY, antithymocyte globulin, and total-body irradiation. Bitan et al26
reported survival with no active disease of three patients with FA and MDS (no cytogenetics reported) at 45, 50, and 96 months after HCT; patients were conditioned with CY, fludarabine, and antithymocyte globulin (one had graft failure and received salvage treatment with a second HCT).
The current study demonstrates that long-term survival is achievable in patients with FA and cytogenetic abnormalities, MDS, or acute leukemia after HCT and that younger age is associated with better outcome, even in patients with acute leukemia (). In our study, related donor HCT recipients had primary and secondary graft failure rates that are within the ranges previously reported in the general FA population.41–44,51
) Because of small numbers, we cannot draw definitive conclusions on engraftment rates among unrelated donor and cord blood HCT recipients.
Our study demonstrates that, among matched related donor HCT recipients, patients with FA who only have cytogenetic abnormalities have better survival than patients who have MDS or leukemia (). This observation is consistent with a report by Alter et al13
on 41 patients with FA with cytogenetic abnormalities, MDS, or both. The presence of MDS had an adverse impact on survival, with an estimated 5-year survival of 9%, compared with 92% for patients who had not developed MDS. Cytogenetic abnormalities had a lesser impact and were associated with an estimated 5-year survival of 40% compared to 94% in patients without cytogenetic abnormalities. However, that study did not address the impact of HCT on survival among those patients.13
Although patients with FA fare better with low-intensity conditioning,17,24,39,40
) earlier studies suggested that the presence of cytogenetic abnormalities, MDS, or leukemia required more intensive conditioning.16,21
) In our analysis, however, the use of radiation therapy did not improve outcome. In a previous CIBMTR study, Pasquini et al41
similarly concluded that the use of radiation was not associated with improved outcomes in patients with FA. This is particularly pertinent in this patient population where radiation has been implicated in the development of new cancers after transplantation.11,19,52,53
In addition, the use of fludarabine, which has been suggested to improve HCT outcome for patients with FA in matched related and unrelated HCT,18,42–44,54,55
) was not associated with a survival advantage in our study. However, these results should be interpreted with caution given the small sample size.
Despite its limitations, this is the largest study of transplantation outcomes in patients with FA and cytogenetic abnormalities, MDS, or leukemia. The data indicate that HCT can lead to long-term survival among these patients. Younger patients and recipients of HLA-matched related donor HCT who have cytogenetic abnormalities only have better long-term survival.
However, even with these encouraging results, the superior results of HCT in patients with FA without pretransplantation cytogenetic abnormalities, MDS, or leukemia suggest that the optimal timing of HCT in patients with FA should be when signs of bone marrow failure develop (eg, need for blood products support) and before the development of any cytogenetic abnormalities, MDS, or leukemia.