12-phase flow (12)

1. 1FRAME
   Frame as acquired bone-marrow failure: pancytopenia + hypocellular marrow without fibrosis/infiltration/dysplasia. Establish acquired vs inherited, severity tier pending, primary vs secondary (drug/toxin/viral/pregnancy/seronegative-hepatitis) (BSH 2024 PMID 38247114; DeZern PMID 34156438)
   inputs: age, inherited_marrow_failure_clues
   actions: workup.pancytopenia
   advance: Bone-marrow-failure framing assigned
2. 2ENTRY
   Triggered by pancytopenia / progressive cytopenia / mucocutaneous bleeding / recurrent infection / symptomatic anaemia, or surveillance visit in known AA (BSH 2024 PMID 38247114)
   inputs: cbc_with_diff
   actions: cascade.labs_command
   advance: Entry trigger captured and CBC reviewed
3. 3CONTEXT
   Capture age, family history + physical IBMFS clues (short stature, nail dystrophy, leukoplakia, café-au-lait), drug/toxin/viral exposure, antecedent hepatitis, pregnancy, prior cytotoxics/radiation, transfusion history, comorbidity, performance status (BSH 2024 PMID 38247114; BSH paeds PMID 29285764)
   inputs: age, inherited_marrow_failure_clues, drug_toxin_viral_exposure, pregnancy_status
   actions: cascade.labs_command
   advance: Aetiology + host context documented
4. 4RED_FLAGS
   Bayesian emergencies: (1) FEBRILE NEUTROPENIA in vSAA/SAA — pre-test sepsis prior high; empiric antipseudomonal within 60 min BEFORE attributing fever elsewhere (BSH 2024 PMID 38247114); (2) intracranial-haemorrhage risk at platelets <10×10⁹/L (or <20k + bleeding/fever) → urgent prophylactic platelet transfusion; (3) fulminant seronegative hepatitis-associated AA (rapidly progressive marrow failure + hepatic failure — high-mortality, urgent IST/HSCT route) (hep-AA PMID 32925550); (4) new circulating blasts / rapidly evolving dysplasia → clonal evolution to MDS/AML route
   inputs: temperature, platelet_count, absolute_neutrophil_count
   actions: workup.neutropenic_fever
   advance: Emergencies excluded or stabilised
5. 5INITIAL_WORKUP
   CBC + differential + reticulocyte (absolute) + blood film (exclude blasts/dysplasia/schistocytes); LFTs + viral hepatitis/EBV/CMV/HIV/parvovirus B19 serology; B12/folate/copper; LDH/haptoglobin + DAT; vitamin/autoimmune screen; pregnancy test; type & screen (BSH 2024 PMID 38247114; DeZern PMID 34156438)
   inputs: cbc_with_diff, reticulocyte_count, liver_function_tests
   actions: panel.cbc, panel.lft, cascade.labs_command
   advance: First-line labs resulted
6. 6BRANCHING_WORKUP
   Bone-marrow aspirate + TREPHINE biopsy (cellularity <25% — or <50% with <30% haematopoietic cells — without fibrosis/infiltration) + cytogenetics/FISH + flow + somatic-mutation panel (exclude hypoplastic MDS); peripheral-blood GPI-anchor flow for PNH clone (present ~1/3 of AA — quantify + serially monitor); chromosomal-breakage DEB/MMC (Fanconi) + telomere length (dyskeratosis congenita) + germline panel (GATA2/SBDS) in age-appropriate / familial / atypical cases; copper/zinc; route splenomegaly if present (BSH 2024 PMID 38247114; DeZern PMID 34156438)
   inputs: bone_marrow_cellularity, pnh_clone_flow, inherited_marrow_failure_clues
   actions: workup.pancytopenia, workup.splenomegaly
   advance: Marrow + PNH + IBMFS work-up complete
7. 7DIFFERENTIAL
   Partition pancytopenia + hypocellular marrow: acquired AA (idiopathic), hypoplastic MDS (cytogenetic clone / dysplasia / somatic mutations), PNH / AA-PNH overlap (GPI-deficient clone, haemolysis), inherited marrow failure (Fanconi / dyskeratosis congenita / SDS / GATA2), drug/toxin/radiation-induced, seronegative hepatitis-associated, large-granular-lymphocyte leukaemia, hypocellular-presenting acute leukaemia, B12/copper deficiency, infiltrative/fibrotic marrow, pregnancy-associated, autoimmune (SLE) (BSH 2024 PMID 38247114; DeZern PMID 34156438)
   inputs: bone_marrow_cellularity, pnh_clone_flow
   actions: workup.pancytopenia, protocol.ttp
   advance: Terminal diagnosis + aetiology assigned
8. 8RISK_STRATIFICATION
   Camitta severity drives the treatment fork: NON-severe (does not meet SAA), SEVERE AA = hypocellular marrow + ≥2 of [ANC<0.5×10⁹/L, plt<20×10⁹/L, retic<20×10⁹/L (or <1%)], VERY-SEVERE AA = SAA + ANC<0.2×10⁹/L. Combine with age, HLA-matched-sibling availability, comorbidity to choose HSCT vs IST (Camitta PMID 2893118; ASTCT 2024 PMID 39307421; BSH 2024 PMID 38247114)
   inputs: absolute_neutrophil_count, platelet_count, reticulocyte_count, age, hla_typing_sibling_donor
   actions: panel.cbc
   advance: Severity tier + donor status + therapy fork set
9. 9TREATMENT
   vSAA/SAA + young + HLA-matched-sibling donor → first-line allogeneic HSCT (5-y OS >90% young MSD; ASTCT 2024 PMID 39307421). Otherwise IST = horse-ATG + ciclosporin + eltrombopag UPFRONT (RACE PMID 34986284: 3-mo CR 22% vs 10%, 6-mo ORR 68% vs 41%; Townsley PMID 28423296 day-1 cohort 6-mo CR 58%/ORR 94%; horse-ATG > rabbit-ATG — Scheinberg PMID 21812672 ORR 68% vs 37%, 3-y survival 96% vs 76%). Non-severe AA requiring treatment: ciclosporin ± eltrombopag or observe. Refractory/relapsed: alternative-donor / haploidentical HSCT, second IST course, eltrombopag salvage. Supportive: irradiated leucodepleted CMV-safe transfusion (restrictive thresholds; AVOID family-donor products pre-HSCT), neutropenic-fever empiric protocol, antifungal/antiviral prophylaxis, iron chelation if transfusion-dependent. Fanconi/IBMFS: DOSE-REDUCE alkylator/irradiation conditioning (BSH paeds PMID 29285764)
   inputs: age, hla_typing_sibling_donor, absolute_neutrophil_count, platelet_count
   actions: panel.cbc
   advance: Definitive therapy + supportive plan executed
10. 10DISPOSITION
    Inpatient for IST induction (ATG serum-sickness monitoring), febrile neutropenia, severe bleeding, HSCT conditioning, fulminant hepatitis-AA; outpatient haematology for non-severe AA, stable IST monitoring, surveillance (BSH 2024 PMID 38247114)
    inputs: absolute_neutrophil_count, temperature
    actions: workup.neutropenic_fever
    advance: Disposition + care setting set
11. 11MONITORING
    CBC + differential + reticulocyte (response timing — first response often 3-6 mo on IST; RACE PMID 34986284); ciclosporin trough levels + renal/hepatic function; eltrombopag LFTs + clonal-evolution surveillance (cytogenetics/marrow if cytopenias worsen or dysplasia emerges); serial PNH-clone flow; transfusion burden + ferritin; ATG serum-sickness watch d7-14 (BSH 2024 PMID 38247114; DeZern PMID 34156438)
    inputs: cbc_with_diff, reticulocyte_count
    actions: panel.cbc, panel.renal
    advance: Monitoring cadence documented
12. 12FOLLOWUP
    Long-term clonal-evolution surveillance (MDS/AML/PNH — periodic marrow + cytogenetics + flow); response reassessment at 3/6/12 mo (re-treat or escalate non-responders); taper ciclosporin slowly to limit relapse; vaccination/fertility counselling; transition paediatric → adult care; lifelong haematology follow-up given late clonal/relapse risk (BSH 2024 PMID 38247114; ASTCT 2024 PMID 39307421)
    inputs: cbc_with_diff
    actions: panel.cbc
    advance: Long-term surveillance plan documented