Successful allo-HSCT with a minimal myeloablative conditioning regimen in an adult patient with Fanconi’s anemia

Fanconi’s anemia (FA) is an autosomal recessive (and rarely X-linked) disorder, usually characterized by several congenital malformations, progressive BM failure and an increased incidence of malignancies. Cells from FA patients are characterized by chromosomal instability and marked sensitivity to DNA crosslinking alkylating agents such as mitomycin C1, which is pathognomonic. The median age at diagnosis of FA is under the age of 7 years; the reported age range is up to 56 years.2 A report from the International Fanconi Anemia Registry revealed that nearly 40% of patients had no reported physical findings.3 The heterogeneity of symptoms and the variety of the clinical course may lead to difficulties in diagnosing FA, especially in adult patients.

Here, we describe a case of adult FA without any reported physical findings receiving allo-HSCT from an unrelated donor after a minimal myeloablative conditioning regimen.

The patient was admitted to a reference hospital at the age of 25 years with a chief complaint of general fatigue. The patient’s general appearance was normal with no skeletal anomaly, except for slight gross skin pigmentation. Laboratory findings revealed severe anemia (hemoglobin 2.2 g/dL) with an elevated mean corpuscular volume (104 fL), and decreased number of both WBC (2.2 × 106/L) and platelet (1.1 × 1010/L). Biopsy of BM revealed a severe hypocellularity, and consequently a diagnosis of aplastic anemia was made. Notably, the abnormal chromosomal breakage test with mitomycin C with patient’s PBMCs strongly suggested the chromosomal fragility of somatic cells (21 breaks/gap out of 45 cells in the patient, 22 breaks/gap out of 100 cells in the normal control). Because an HLA-identical sibling donor was available, immunosuppressive therapy using antithymocyte globulin, CYA and G-CSF was initiated 2 months after admission. Androgen therapy that was initiated after failure of the immunosuppressive therapy also failed. Eight months later, the patient was referred to our hospital for allo-HSCT with an unrelated donor.

The abnormal chromosomal breakage test is indicative of FA among patients with BM failure syndrome,4 and a subsequent diepoxybutane test for peripheral T-lymphocytes also revealed the increase sensitivity to the reagent as well, and he lacked FANCD2 monoubiquitination, which has been developed for a rapid diagnosis and subtyping screen for FA based on the FA signaling pathway.5 These findings lead to a definitive diagnosis of FA.4 Although awaiting definitive proof of FA, he had no alternative but to receive frequent blood transfusions (10 RBC units/month, 80 platelet concentrates/month).

The first-line treatment for patients under the age of 40 years with severe AA refractory to immunosuppressive therapy is an unrelated allo-HSCT. However, accumulated evidence has demonstrated that a survival rate for FA patients having received unrelated allo-HSCT was only 33%.6 A recent pilot study of unrelated allo-HSCT using a minimal myeloablative conditioning regimen for FA patients reported that the 1-year OS was 96.3%;7 thus, we proceeded with unrelated allo-HSCT at the age of 26 years. The number of transplanted nucleated cells was 1.78 × 108/kg. The patient was conditioned with a minimal myeloablative conditioning regimen consisting of 3-Gy thoraco–abdominal irradiation on day −8, 25 mg/m2 of i.v. fludarabine from day −7 to day −2, 10 mg/kg of i.v. cyclophosphamide from day −5 to day −2, and 1.25 mg/kg of antithymocyte globulin from day −5 to day –2.7 As prophylaxis for acute GVHD, administration of 0.02 mg/kg FK506 was started on day −1 and a short course of methotrexate was given on days +1, +3, +6 and +11. The patient also received 5 μg/kg of G-CSF from day +5. Neutrophil and platelet engraftment was achieved on days +23 and +46, respectively. Complete donor chimerism in BM cells was achieved on day +64. Despite several other regimen-related toxicities (grade 3 sepsis, grade 3 mucositis, grade 3 pulmonary invasive aspergillosis, grade 2 convulsion during BM cells infusion), the patient was discharged on day +73. He is healthy without any immunosuppressant drug, blood transfusion or secondary malignancy 4 years after HSCT.

Even though G-CSF alone or combined with EPO and/or androgens may be helpful, allo-HSCT represents the only alternative, which is capable of providing corrected long-term hematopoiesis in FA. Results of allo-HSCT from alternative donors have still been insufficient, with a survival rate of 29–38% because of an increased rate of graft rejection, severe GVHD or opportunistic infections.6, 8 However, an increased OS of 72.2–96.3% has been achieved by unrelated allo-HSCT using fludarabine-based conditioning regimen.7, 9, 10

Making a prompt and definite diagnosis of FA in patients with BM failure is pivotal, especially in patients who take advantage of unrelated allo-HSCT using minimal myeloablative conditioning for the following reasons:

  1. 1)

    Immunosuppressive therapy is revealed to be ineffective, rather time consuming and harmful, considering the requirement for frequent blood transfusions and immunosuppressive therapy-related mortality because of life-threatening infection.

  2. 2)

    Sibling donors might be also affected with FA.

  3. 3)

    Conventional myeloablative conditioning regimens increase the regimen-related mortality.

  4. 4)

    Higher potential risk of secondary malignancies following HSCT because of the genetic background.

In conclusion, for practical hematologists who manage young adult patients with severe AA, FA must be actively ruled out, particularly in patients between the ages of 20 and 40 years, who are the best candidates for unrelated allo-HSCT using minimal myeloablative conditioning.


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Correspondence to N Arima.

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Maekawa, K., Yoshimitsu, M., Fujiwara, H. et al. Successful allo-HSCT with a minimal myeloablative conditioning regimen in an adult patient with Fanconi’s anemia. Bone Marrow Transplant 47, 159–160 (2012).

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