Alemtuzumab As Therapy for Mixed Chimerism After Hematopoietic Stem Cell Transplantation for Fanconi Anemia (FA)

Background: The development of mixed chimerism/graft rejection is not uncommon following transplant for FA. A proportion of children with FA demonstrate somatic mosaicism, carrying two populations of lymphocytes, one with a true DEB sensitive phenotype, and a second population of lymphocytes with a DEB resistant phenotype, often arising from a somatic gene conversion event in compound heterozygous cells, generating a single normal FA allele.  Preparative regimens for FA transplants are typically dose-reduced to accommodate the increased toxicity associated with the FA phenotype, and while sufficient to clear lymphocytes with an FA phenotype, may not be adequate for revertant or mosaic lymphocytes with a revertant or mosaic phenotype. We describe a series of three children with FA who received Alemtuzumab for treatment of mixed chimerism associated with an abrupt rise in their absolute lymphocyte count (ALC), likely due to expansion of host lymphocyte populations with a DEB resistant mosaic phenotype.

Methods: Patients, donor and transplant characteristics are shown in Table 1. Conditioning regimen included busulfan 0.8-1.0 mg/kg/dose Q 12hrs (with pharmacokinetic monitoring) x 4 doses, fludarabine 35 mg/m2/dose, cyclophosphamide 10 mg/Kg/dose, and ATG 2.5 mg/kg/dose once daily x 4 doses.

Results: After initial complete engraftment, each child displayed an acute elevation of their ALC at 50, 50 and 36 days after transplant, concurrent with a rapid decline in donor chimerism (see Table 1 ). Patients received alemtuzumab 0.8 – 1.0 mg/kg over the course of 3-5 days, resulting in expected lymphopenia which corresponded with improving donor chimerism by the end of the first week of therapy. First 2 patients have continued to have full donor chimerism (>99% donor) for > 3 months. Patient # 3 although showed improving chimerism (up to 81.4%), did not recover from secondary graft failure and went on to receive second transplant from a 6/8 HLA matched parent donor.  After initial engraftment of 100%, she again had an acute elevation of ALC (day 16) along with decrease in chimerism to 85%. This time alemtuzumab was used promptly, leading to successful outcome (Table 1).

Conclusion: In patients with Fanconi Anemia undergoing transplant, the development of mixed chimerism may be due to incomplete lympho-depletion and return of recipient lymphocytes.  In these cases, prompt and aggressive lymphoid depleting therapy is warranted to prevent graft rejection.