How we diagnose and manage FA patients with MDS and AML.aWe defined provisional cytogenetic/molecular categories by reference to MDS/AML literature in FA6,7,27,33,34 and non-FA49,50 patients (also see text). RUNX1-abn can include RUNX1 gene mutation, deletion, and/or translocation.7 Genetic reversion (hematopoietic somatic mosaicism) is not indicated in the figure to keep it simple. bThe timing of BM monitoring is discussed, especially because repeated aspiration is poorly tolerated in children, adolescents, and young adults.40 The overall consensus is that a 1-year basis of BM aspirate is reasonable and should be adapted in response to blood cell count changes, myelodysplasia signs, increased blast proportion, and/or cytogenetic evidence of clonal evolution. Conversely, BM monitoring is likely to be slightly delayed in FA children under age 10 years (except in BRCA2/FANCD1 patients), given the rarity at this age and relatively slow pace of clonal progression. cThe classical reduced-intensity conditioning (RIC) regimen consists of 90 mg/m2 of fludarabine (30 mg/m2 on days −4, −3, and −2) and 40 mg/kg of cyclophosphamide (10 mg/kg on days −5, −4, −3, and −2) in the case of matched related donor. One might argue that, in the case of MDS/AML, low-dose cyclophosphamide/fludarabine alone would not suffice as conditioning therapy due to the substantial number of residual host cells early after transplant with this approach and the risk of relapse; an alternative is the use of TBI (2-3 Gy) in patients with MDS/AML and an HLA- matched sibling donor.16,48 In the case of matched unrelated donor, the conditioning regimen consists of fludarabine (120 mg/m2), cyclophosphamide (40 mg/kg), and TBI (2 Gy). GVHD prophylaxis consists of mycophenolate acid and cyclosporine. Anti-thymocyte globulin is used in total doses of 5 mg/kg in the case of matched unrelated donor only. Others favor ex vivo T-cell depletion with an add-back of T cells to achieve a fixed graft T-cell dose of 1 × 105 CD3 cells per kilogram recipient.62 In the case of CB HSCT, we do not use anti-thymocyte globulin in the conditioning regimen. dOthers do not recommend cytoreduction, except in patients with BRCA2 mutations16,48,62 ; the sequential strategy comprising pretransplant chemotherapy with fludarabine (30 mg/m2 per day for 5 days) and cytarabine (1 g/m2 twice per day for 5 days) with granulocyte colony-stimulating factor injections (FLAG), followed 3 weeks later by an RIC regimen (4 days of cyclophosphamide, 10 mg/kg; 4 days of fludarabine, 30 mg/m2; and TBI, 2 Gy) delivered during chemotherapy-induced aplasia. Again, anti-thymocyte globulin is used in total doses of 5 mg/kg in the case of matched unrelated donor only. In the case of CB HSCT, we do not use anti-thymocyte globulin in the conditioning regimen. eScreening for malignancies, including oropharyngeal, dental, and gynecological examinations, forms part of long-term patient care. Long-term multidisciplinary surveillance is also mandatory for all patients post-HSCT.40 The multiple problems in early age, subsequent requirements for HSCT, and continuing poor prognosis in survivors due to cancer susceptibility are a source of stress for FA patients and their families. Adequate psychosocial support and a coordinated, multidisciplinary team with dedicated physicians are the cornerstones to successful management.40 CGH, comparative genomic hybridization; FLAG, fludarabine/cytarabine/granulocyte colony-stimulating factor; GVHD, graft-versus-host disease; SIC, severe isolated cytopenia; SNP, single nucleotide polymorphism.
