Fanconi Anemia Treatment in India and UAE | Complete Patient Guide

• 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

• Adequate organ function: LVEF ≥45% on 2D Echocardiography (ECHO); FEV1/FVC ≥60% on pulmonary function tests (PFTs); serum creatinine within 1.5× upper limit of normal; total bilirubin <2× ULN; no active uncontrolled infection

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

• 2D Echocardiogram (LVEF assessment)

• Pulmonary function tests (spirometry and DLCO)

• CT scan of chest, abdomen, and pelvis (baseline solid tumour screening)

• Liver and kidney function panels, coagulation profile

• Infectious disease serology: CMV, EBV, HSV, VZV, HIV, Hepatitis B (HBsAg, Anti-HBc), Hepatitis C

• Dental and ENT evaluation (head/neck SCC surveillance)

• Gynaecological evaluation for female patients aged >13 years (HPV-related SCC risk)

• Fertility counseling and, where clinically feasible, gonadal tissue cryopreservation (RIC protocols may preserve some fertility potential vs. myeloablative regimens)

Contraindications:

• Active invasive fungal or bacterial infection not controlled with appropriate antimicrobials

• Active, progressive malignancy beyond MDS/AML (separate oncological management required first)

• Severe, irreversible organ dysfunction (LVEF <35%, end-stage hepatic cirrhosis, ESRD on dialysis)

• No available donor (allogeneic HSCT is by definition donor-dependent; cord blood and haploidentical programs expand access but center expertise is mandatory)

• Patient or family refusal of blood products (relative contraindication; requires ethical and multidisciplinary review)

**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.

**5. Gene Therapy (Investigational – Not Standard of Care)** Autologous HSCT following ex-vivo lentiviral vector-mediated correction of the FANCA gene (the most common FA subtype, accounting for ~65% of patients) is under active Phase II clinical investigation, most notably through the Spanish CIEMAT/CIBERER program and its international collaborators. Gene therapy eliminates GvHD risk entirely and removes donor dependency. As of the current date, it is not yet approved for routine clinical use but represents the most transformative horizon in FA management. Patients with documented FANCA mutations should be informed of ongoing trial eligibility.

**6. Graft-versus-Host Disease (GvHD) Prevention and Management** GvHD prophylaxis is individualized based on donor type: Calcineurin inhibitor (Tacrolimus, target trough 8–12 ng/mL) + MMF for MSD; Tacrolimus + Methotrexate (MTX, 5–15 mg/m² on Days +1, +3, +6, +11) for MUD; PTCy + Tacrolimus + MMF for haploidentical. Acute GvHD (grades II–IV) is treated with high-dose methylprednisolone (2 mg/kg/day) as first-line; steroid-refractory acute GvHD is managed with Ruxolitinib (JAK1/JAK2 inhibitor, FDA/EMA-approved second-line), Extracorporeal Photopheresis (ECP), or anti-thymocyte globulin (ATG). Chronic GvHD management follows IBMTR/BMT CTN protocols.

**7. Infectious Prophylaxis and Supportive Care (FA-Specific Considerations)** All FA transplant patients receive mandatory prophylaxis: antifungal (micafungin or voriconazole during neutropenia, transitioning to fluconazole or posaconazole after engraftment), antiviral (acyclovir for HSV/VZV; valganciclovir for CMV-seropositive donor-recipient pairs with weekly CMV PCR monitoring), and Pneumocystis jirovecii pneumonia (PJP) prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX, resumed after engraftment). Levofloxacin antibacterial prophylaxis during neutropenia is center-dependent. IVIG supplementation is given if IgG <400 mg/dL during immune reconstitution.

**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)**

• Patient admitted to the Bone Marrow Transplant Unit (BMTU), a laminar-airflow HEPA-filtered positive-pressure isolation room

• Baseline vitals, weight, and organ function re-assessed; Hickman/CVC patency confirmed

• Infectious prophylaxis initiated: oral fluconazole or micafungin IV, acyclovir, TMP-SMX suspended during conditioning (resumed after engraftment)

• Conditioning regimen administered according to protocol (e.g., Flu/Cy or Flu/Cy/TBI):

- Day -6 to -2: Fludarabine 30 mg/m²/day IV over 30 minutes (total 150 mg/m²)

- Day -5 and -4: Cyclophosphamide 10 mg/kg/day IV (total 40 mg/kg) with MESNA uroprotection and aggressive IV hydration

- Day -1 (if TBI included): Low-dose TBI 2 Gy delivered by linear accelerator (LINAC) in a single fraction under radiation oncology supervision

- Day 0: Rest day (no conditioning agents)

• Hyperhydration, antiemetics (ondansetron, aprepitant), and electrolyte management throughout conditioning

• Daily CBC, metabolic panel, and clinical assessment

**Phase 3: Stem Cell Infusion – Transplant Day (Day 0)**

• Donor stem cells (PBSC or bone marrow harvest) prepared in the cell processing laboratory under GMP conditions; viability assessed by flow cytometry (CD34+ cell count target: ≥2–5 × 10⁶ CD34+ cells/kg recipient body weight for PBSC)

• Infusion performed at bedside under continuous nursing and physician supervision, typically over 1–4 hours via the tunneled CVC

• Vital signs monitored every 15 minutes throughout infusion; pre-medication with hydrocortisone and diphenhydramine to reduce infusion reactions

• ABO incompatibility between donor and recipient requires red cell depletion or plasma reduction of the graft in the cell processing lab before infusion

**Phase 4: Engraftment Phase – Critical Neutropenic Period (Days +1 to +30)**

• Absolute neutropenia (ANC <200/µL) expected from Day +7 to +14; highest infection risk period

• Daily CBC; transfusion support with irradiated and leukocyte-depleted packed red cells (threshold Hb <7–8 g/dL) and platelets (threshold <10,000/µL or bleeding)

• G-CSF (filgrastim) may be administered from Day +5 at transplant physician discretion to accelerate neutrophil engraftment

• GvHD prophylaxis immunosuppressants initiated per protocol (Tacrolimus from Day -3; MTX on Days +1, +3, +6, +11 for MUD)

• Engraftment defined as: ANC ≥500/µL for 3 consecutive days (typically achieved Day +14 to +21 for MSD PBSC)

• Weekly chimerism studies (STR-PCR) from Day +14 to confirm donor engraftment percentage; target: ≥95% donor chimerism

• CMV surveillance by weekly quantitative PCR; pre-emptive valganciclovir or ganciclovir initiated if CMV DNA >150–200 IU/mL on 2 consecutive tests

**Phase 5: Early Post-Engraftment Monitoring (Days +30 to +100)**

• Transition from inpatient to closely supervised outpatient follow-up (patient must remain within 30–60 minutes of the transplant center)

• Clinical assessment 3×/week initially, tapering to 2×/week and then weekly as stability confirmed

• Bone marrow biopsy and aspirate with chimerism at Day +30 and Day +100 to assess engraftment quality and exclude MDS relapse

• Tacrolimus dose tapering begins at Day +90–120 in absence of GvHD

• Immunoglobulin levels (IgG, IgM, IgA) and lymphocyte subset reconstitution panel (CD3, CD4, CD8, CD19, NK cells) at Day +100

• Vaccination plan discussed (deferred minimum 12 months post-transplant and until immunosuppression discontinued)

• Surveillance for late effects: thyroid function tests (TFTs), bone density (DEXA scan, if TBI used), growth hormone assessment (pediatric patients)

**Phase 6: Fit-to-Fly Assessment and Discharge for International Travel (Weeks 12–20)**

• Fit-to-fly clearance issued by the transplant physician only when ALL of the following criteria are met:

- Stable donor chimerism ≥95% on at least 2 consecutive assessments

- ANC consistently ≥1,000/µL without growth factor support

- No active GvHD requiring escalation of immunosuppression

- No active viral reactivation (CMV, EBV, adenovirus) by PCR

- Oral medication tolerance confirmed (patient can absorb all oral immunosuppressants reliably)

- Confirmed follow-up plan with a haematologist or transplant physician in the home country who has received the complete transfer of care documentation

• GAF Healthcare arranges the medical transfer summary, continuation prescriptions (Tacrolimus, antifungal, antiviral, TMP-SMX), and airline medical clearance letter

• Long-term follow-up: Annual FA-specific cancer surveillance (head and neck SCC, gynaecological SCC in female patients) at a local oncology center, coordinated through GAF Healthcare's telemedicine follow-up program