Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by progressive pancytopenia, congenital malformations, chromosomal instability and predisposition to the development of malignancies. Hematopoietic cell transplantation (HCT) from a matched sibling donor is the only curative approach for the hematological abnormalities associated with FA; unfortunately only 25% to 35% of FA patients have a compatible cord blood or marrow donor.1 Successful outcome for transplantation in FA patients with non-matched sibling donors is in the range of 25-40%; graft rejection, high risk of developing graft-versus-host disease (GVHD) and regimen-related toxicities have been the greatest obstacles.2 Umbilical-cord blood from unrelated donors can restore and sustain hematopoietic function, with a low risk of GVHD.3 Studies performed at FHCRC showed that sublethal doses of total body irradiation (TBI, 200 cGy) followed by potent post-transplant immunosuppression (cyclosporin A, CsA plus mycophenolate mofetil, MMF) were able to prevent GVHD and graft rejection, allowing stable mixed chimerism. Fludarabine (FLU)-based conditioning regimens, capable of intense T cell immunosuppression, have been used successfully for various non-malignant diseases, with minimal toxicity and stable and durable engraftment.4,5 FA patients are natural candidates for non-myeloablative transplantation, because of their cellular hypersensitivity to DNA cross-linking agents, such as cyclophosphamide (CFA) and radiotherapy.6
Considering all these studies, we decided that transplantation using unrelated cord blood, a non-myeloablative conditioning regimen and intense immunosuppression post transplant were appropriate for a patient with FA.
A 5-year-old girl with FA determined by DEB fragility and life-threatening marrow failure was referred to our center. She had no compatible related donor, but an HLA-A, B and DRB1 identical unrelated cord-blood had been identified at London Cord Blood Bank. Prior to transplant she had received approximately 60 units of packed red blood cells and oxymetholone and prednisone for 3 years. An abdominal computerized axial tomography study had revealed four nodules in the liver, interpreted as androgen-related hepatic tumors. Conditioning consisted of FLU (30 mg/m2 i.v. day from days -4 to -2), and low dose TBI (200 cGy) on day -1. Cord-blood cells (1.36 ´ 107/kg recipient weight nucleated cells, and 0.061 ´ 106/kg recipient weight CD34+ cells) were infused on day zero. GVHD prophylaxis was CsA (1.5 mg/kg/day i.v. from day -3 to day zero, then p.o. from day +1 to +100, tapering off on day +177) and MMF (30 mg/kg/day p.o. from day zero to day +40, tapering off on day +96). The regimen was well tolerated; mucositis, hemorrhagic cystitis and acute GVHD were not observed. She received 13 related single-donor platelet transfusions during her admission. The lowest granulocyte count was observed on day +6, and the first evidence of WBC engraftment was on day +16. Discharge occurred on day +23. On day +232, her Karnofsky score was 100%. Details of peripheral blood counts and engraftment are given in Table 1.
Hematopoietic stem cell transplantation, from related marrow or umbilical cord blood, is considered the best therapy for FA patients. However, their exquisite hypersensitivity to conditioning agents, with well-known toxic effects (severe mucositis, gastrointestinal lesions and hemorrhage, fluid retention, cardiac failures and hemorrhagic cystitis) has been an obstacle.7 In our experience, decreasing the doses of CFA without irradiation has resulted in lower rates of toxicity and acute and chronic GVHD, with good engraftment.8,9,10 However, we have been limited to the setting of related transplantation.
Results of transplants from donors other than HLA-identical siblings are poor. The EBMTR reported 76 FA patients transplanted with marrow from unrelated donors. Primary graft failure was observed in 11 patients, and despite the use of CsA and methotrexate ± prednisone, approximately 55% developed grade II to IV acute GVHD. The overall event-free survival was 23%.11 MacMillan et al12 also reported the results of 29 patients with FA receiving transplants from alternate donors, and the probability of survival of the entire group at 1 year was 34%. Our own experience transplanting five patients with unrelated marrow is dismal, all five having died secondary to GVHD and infection.
Cord blood transplants from unrelated donors characteristically lead to good engraftment (approximately 80% of patients) and reduced severity of acute and chronic GVHD (23% and 25%, respectively). However, in FA patients poor engraftment secondary to host factors has been reported.3
The group from FHCRC, together with collaborators at the University of Leipzig, Germany, demonstrated the feasibility of inducing mixed chimerism in unrelated transplants, utilizing FLU and sublethal irradiation as conditioning, and CsA and MMF post-transplant. FLU is a purine analogue that induces severe T cell immunosuppression, inhibiting DNA replication and repair. It may function as a radiosensitizer and has been used successfully as conditioning for non-myeloablative transplants.5,13 These results led the FHCRC group to design a new protocol for FA patients with unrelated donor stem cell transplantation. We used the same program (FLU and sublethal irradiation, associated with CsA and MMF post-transplant) to treat our patient, but gave unrelated cord blood. The patient had minimal complications during the transplant period, with no acute or chronic GVHD, and engraftment occurred gradually (Table 1). Auerbach et al14 published the data from a joint study with our group, demonstrating that 62% of our patients belong to the FA-A complementation group, and there is a trend suggesting that most FA patients in Brazil have a better prognosis. This fact may explain the favorable transplant response of our patient. However, Aker et al13 reported a FA patient who was transplanted after conditioning with a FLU-based protocol, who also had minimal transplant-related toxicity.
The ideal conditioning regimen and post transplant immunosuppression for FA patients are yet to be determined. Efforts must be directed towards tailored regimens, based on patient sensitivity and donor compatibility.
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