Лучшие больницы для «Fanconi Anemia Treatment» в Мумбаи, Индия

Fanconi Anaemia is an autosomal recessive (and occasionally X-linked) DNA repair disorder caused by biallelic pathogenic variants in one of at least 22 FANC genes (most commonly FANCA, FANCC, FANCG, and FANCD2), which encode proteins of the FA/BRCA DNA damage response pathway. The cellular inability to repair interstrand DNA crosslinks leads to progressive bone marrow failure, presenting clinically as pancytopenia (severe anaemia, thrombocytopenia, and neutropenia), a markedly elevated risk of myelodysplastic syndrome (MDS), and acute myeloid leukaemia (AML). Patients also carry a lifetime predisposition to solid tumours, particularly squamous cell carcinomas of the head, neck, and gynaecological tract, underscoring the urgency of curative intervention before clonal haematopoietic evolution occurs.

• Confirmed genetic diagnosis of Fanconi Anaemia: biallelic pathogenic FANC gene variants identified by next-generation sequencing (NGS) gene panel; FA confirmed by chromosomal breakage test using diepoxybutane (DEB) or mitomycin C (MMC) on peripheral blood lymphocytes (the gold-standard diagnostic assay)
• Moderate-to-severe aplastic anaemia (MSAA/SAA): absolute neutrophil count (ANC) <1,000/µL, platelet count <50,000/µL, or transfusion dependence (>8 RBC units per year)
• Absence of advanced MDS (IPSS-R intermediate or higher) or AML at time of transplant (active transformation is a relative contraindication requiring disease-specific cytoreduction first)
• Age: Pediatric patients (1–18 years) carry the best outcomes; adult transplantation (18–40 years) is feasible at experienced centers; transplant is generally not offered beyond age 50 due to exponentially rising RIC toxicity
• Availability of a suitable donor: HLA-matched sibling donor (MSD, 6/6 or 10/10) is first choice; 8/8 matched unrelated donor (MUD via NMDP/DKMS registry); haploidentical family donor as a last resort
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Required Pre-Transplant Diagnostic Workup:

• Complete blood count (CBC) with reticulocyte count and peripheral smear
• Bone marrow biopsy and aspirate with cytogenetics (karyotype, FISH for monosomy 7, del(7q), trisomy 3q)
• High-resolution HLA typing (allele-level, 10/10 loci) of patient and all potential donors
• Chromosomal breakage test (DEB/MMC) if diagnosis not previously molecularly confirmed
• Comprehensive NGS FANC gene panel
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**1. Matched Sibling Donor (MSD) HSCT with FA-Specific RIC – Gold Standard** The preferred and most evidence-supported approach. The Fludarabine-Cyclophosphamide (Flu/Cy) conditioning backbone uses Fludarabine 150 mg/m² (30 mg/m²/day × 5 days) combined with Cyclophosphamide at steeply reduced doses of 40 mg/kg total (compared to 120–200 mg/kg in non-FA myeloablative regimens), exploiting Fludarabine's profound T-cell immunosuppression to permit engraftment while cyclophosphamide provides additional myelosuppression at a tolerable DNA-damage burden. This Flu/Cy RIC protocol was pioneered at the University of Minnesota and has since become the global FA transplant standard. Published OS rates with MSD using this protocol exceed 85–90% in pediatric cohorts. Stem cell source is preferentially peripheral blood stem cells (PBSC) mobilized with G-CSF or bone marrow harvest depending on donor age and center preference.

**2. Matched Unrelated Donor (MUD) HSCT with Flu/Cy ± Low-Dose TBI** When an MSD is unavailable (approximately 70–75% of FA patients lack one), a 8/8 or 10/10 HLA-matched unrelated donor sourced through international registries (NMDP, DKMS, WMDA) is pursued. The addition of low-dose Total Body Irradiation (TBI, 2–4 Gy in a single or two fractions) to the Flu/Cy backbone (Flu/Cy/TBI protocol) enhances graft-versus-host immunosuppression sufficiently to facilitate MUD engraftment while remaining within FA's narrow therapeutic window for DNA-damaging agents. Immunosuppressive prophylaxis typically combines Calcineurin Inhibitors (Tacrolimus or Cyclosporine A) with short-course Methotrexate or Mycophenolate Mofetil (MMF) to prevent GvHD.

**3. Haploidentical Donor HSCT with Post-Transplant Cyclophosphamide (PTCy)** For patients lacking both MSD and MUD, haploidentical HSCT using a first-degree relative (parent or sibling with 50% HLA match) has become feasible through the O'Donnell-Baltimore PTCy platform. In FA patients, PTCy doses must be further reduced (typically 25–50 mg/kg total, divided on Days +3 and +4 post-transplant) from standard non-FA protocols (100 mg/kg) due to FA cellular hypersensitivity to cyclophosphamide's DNA crosslinking activity. Early published data from specialized centers (Cincinnati Children's, Rigshospitalet Copenhagen, and select Indian transplant programs) demonstrate acceptable engraftment and OS rates of 60–70%, establishing haploidentical HSCT as a viable third-line alternative.

**4. Umbilical Cord Blood Transplantation (UCB-HSCT)** Cord blood units from public HLA-matched cord blood banks (NetCord-FACT accredited) are an alternative stem cell source, particularly for pediatric patients lacking MSD or MUD. UCB grafts offer lower GvHD incidence due to immunological naïvety of cord blood T-cells, but carry risks of delayed engraftment and primary graft failure, which are particularly dangerous in the immunocompromised FA patient. Double UCB transplantation or ex-vivo expanded cord blood units (using nicotinamide, StemRegenin-1, or OmniGen platforms) are investigational approaches under evaluation at tertiary FA centers.

**Phase 1: Pre-Transplant Workup and Donor Search (Weeks 1–8 before admission)**

• GAF Healthcare coordinates medical record review by the transplant physician within 48–72 hours of patient inquiry
• Comprehensive diagnostic workup (as listed under candidacy) completed at home country or upon arrival; some centers offer a dedicated 5–7 day pre-transplant evaluation admission
• HLA typing of patient and all potential family donors; if no MSD identified, formal unrelated donor search initiated through international registries (NMDP/DKMS); typical MUD search timeline: 4–8 weeks
• Multidisciplinary team (MDT) discussion: Transplant haematologist, infectious disease specialist, pulmonologist, dentist, and psychologist/social worker
• Patient and family education session: conditioning regimen details, expected side effects, GvHD recognition, isolation protocols, and long-term FA cancer surveillance
• Pre-conditioning interventions: dental extractions (if indicated), treatment of active infections, nutritional optimization (enteral nutrition support if BMI <18.5 or serum albumin <3.0 g/dL)
• Vascular access: placement of a tunneled central venous catheter (CVC, e.g., Hickman line or PICC) under ultrasound guidance

**Phase 2: Hospital Admission and Pre-Conditioning (Days -10 to -1)**