39  Acquired Bone Marrow Failure Syndromes

KEY POINTS
  • Immune aplastic anemia (AA): cytotoxic T-lymphocyte-driven destruction of hematopoietic stem & progenitor cells; diagnosis of exclusion, requires excluding secondary toxicity, inherited BMF syndromes, & MDS
  • Severity classification (modified Camitta): Moderate (any lineage ↓), Severe (≥2 lineages ↓: ANC <0.5 × 10⁹/L, plt <20 × 10⁹/L, retic <60 × 10⁹/L; BMF <25%), Very Severe (ANC <0.2 × 10⁹/L)
  • Diagnosis requires: hypocellular marrow (<25% cellularity), chromosome fragility testing (FA), telomere length testing (TBD), germline genetic testing for inherited BMF syndromes in all patients
  • Severe AA treatment: age ≤40 w/ matched sibling → HCT; age >40 or no donor → hATG + CSA + eltrombopag
  • HCT advantage: reduced relapse risk & avoidance of MDS/PNH clonal evolution; median survival >80% in children, ~50% in adults >40
  • Pure Red Cell Aplasia (PRCA): normochromic/normocytic anemia w/ reticulocytopenia (<10,000/μL); 60-70% response to immunosuppression (CSA ± steroids)

39.1 Introduction

  • BMF syndromes: ↓ cytopenias from failed hematopoiesis, hypocellular BM & ↓ reticulocytes
  • Etiology: immune, inherited (germline), or direct toxicity
  • Manifests: pancytopenia or lineage-specific cytopenias
  • Focus: acquired immune-mediated BMF (AA, PRCA); see Ch 35 for IBMFS

39.2 Aplastic Anemia

39.2.1 Definition & Classification

  • Immune AA: ↓ HSPC dysfunction → hypocellular BM, trilineage cytopenia & ↓ retics
  • Diagnosis of exclusion: exclude 2° toxicity, IBMFS, MDS before diagnosing
Severity ANC Platelets Reticulocytes Marrow Cellularity
Nonsevere (Moderate) Any Any Any <25%
Severe (≥2 of 3) <0.5 × 10⁹/L <20 × 10⁹/L <60 × 10⁹/L <25%
Very Severe* <0.2 × 10⁹/L Any Any <25%

39.2.2 Epidemiology & Etiology

  • Incidence: <2/million/yr (West), 4–6/million/yr (Asia); bimodal (children, elderly)
  • Asian predisposition: possible genetic (HLA, SNPs); no environmental causation identified
  • Equal sex; drug assoc limited evidence (NSAIDs, PTU, anticonvulsants, chloramphenicol)
  • Hep-associated AA: 2–5% (Europe), 4–10% (East Asia); seronegative; delayed onset post-hep

39.2.3 Pathogenesis

  • Immune attack on HSPCs by CTLs → ↓ CD34+, ↓ CFU, impaired progenitors
    • CTL activation produces TNFα & IFNγ → apoptosis via Fas/FasL
    • Trigger unknown; IST efficacy supports immune mechanism
  • Clonal escape enriches PNH clones (PIGA mut), HLA-deficient clones
    • High PNH/BMF co-occurrence from selection pressure
  • Malignant progression risk: fitness-advantaged clones → ↑ MDS/AML

39.2.4 Clinical Presentation

  • Symptoms: anemia (fatigue, weakness), thrombocytopenia (petechiae, epistaxis)
    • Infections w/ very severe ANC <0.2 × 10⁹/L
    • Often asymptomatic at detection; healthy hx, no chemo/XRT
  • Red flags for IBMFS:
    • Dysmorphic features: short stature, radial anomalies, dysplastic nails
    • Skin rashes, oral leukoplakia, pancreatic insufficiency
    • Splenomegaly/hepatomegaly → consider alternate diagnosis
    • Family hx: cytopenias, hematologic/solid malignancy, organ involvement
    • Absence of stigmata ≠ exclude IBMFS (may present as acquired AA/MDS)

39.2.5 Differential Diagnosis & Diagnostic Testing

  • Exclude: PNH, IBMFS (FA, TBD, Shwachman-Diamond, amegakaryocytic TC, GATA2), hypoplastic MDS, reactive causes, LGL leukemia, hairy cell leukemia

  • PB: pancytopenia w/ ↑ relative lymphocytes; otherwise normal

  • BM morphology: hypocellular (<25%), no infiltrate, paucicellular w/o dysplasia

    • Myeloid left-shifted (no ↑ blasts), ↑ mature T cells

  • Flow: ↓ CD34+ (normal phenotype); dysplasia/↑ blasts suggest myeloid neoplasm

  • Karyotype: normal (AA); abnormal favors hypoplastic MDS (trisomy 8, del13q, del20q rare in AA)

  • Specialized testing (exclude IBMFS):

    • DEB test: ↑ breakage → FA diagnosis
    • Telomere length (flow-FISH): <1st%ile (specific TBD), <10th%ile (possible TBD), >10th%ile (unlikely)
    • Immune subsets: identify inborn errors of immunity
    • PNH flow: detects PNH clones; diagnostic help
    • T-LGL assessment: flow + TCR rearrangement if ↑ LGLs; STAT3 mutations common
    • Germline testing: standard; detects IBMFS mutations (~7% pre-transplant cohorts)
      • Best on fibroblasts (distinguish germline/somatic, account mosaicism)
      • Defer only if unavailable & no suspicious clinical/family hx

  • Somatic mutations: ↑ in AA (PIGA, BCOR, BCORL1, DNMT3A, ASXL1)

    • NOT diagnostic MDS unless meet WHO/ICC criteria
    • PIGA/BCOR/BCORL1 favor immune AA diagnosis
    • NGS not standard baseline (won’t guide Tx)

39.2.6 Therapy

  • SAA requires definitive Tx (IST or HCT); w/o Tx → death from infection/hemorrhage
  • Non-severe AA: Tx optional; rare spontaneous remission
  • Moderate AA: occasional spontaneous recovery; transfusion dependence may prompt Tx
  • Decisions based on severity & age:

39.2.6.1 Supportive Care & Blood Products

  • Irradiated, leukodepleted products: ↓ alloimmunization & GVHD risk

  • Avoid family member transfusions: ↑ graft rejection

  • CMV- patients: CMV- or leukodepleted products

  • Antifungal prophylaxis: VSAA (ANC <0.2); AB/AV/PJP role undefined

  • Growth factors (limited role):

    • G-CSF/GM-CSF & ESAs: ↑ serum EPO in AA; poor response; small adjunctive role
    • Corticosteroids: ineffective, ↑ infection; use only for ATG serum sickness
    • Androgens: supportive only; not 1st-line

39.2.6.2 Hematopoietic Stem Cell Transplantation (HCT)

  • Indications: age ≤40 w/ MSD → direct HCT (usually curative)
  • Advantages over IST: ↓↓ relapse, avoids MDS/PNH; risk: GVHD
  • Conditioning (immunosuppressive; enable engraftment):
    • Cy ×4d + ATG or Cy ×2d + Flu + ATG
    • Nonmyeloablative intensity sufficient; avoid TBI/busulfan (↓ 2° malignancy, toxicity)
  • Graft source: BM preferred (↓ GVHD vs PBSC); avoid GVHD in AA
  • Outcomes:
    • MSD: >80–90% survival children; 1/3 chronic GVHD
    • MUD: improved recent outcomes; 2× GVHD risk vs MSD; must do <3mo
    • Adults >40: ~50% long-term survival; ↑ GVHD w/ age
    • Haplo-HCT: improving results, salvage option; moderate TBI 400 cGy may ↓ graft failure
  • Key factors: age, time to transplant (<3mo optimal), allograft type

39.2.6.3 Immunosuppressive Therapy (IST)

  • hATG (horse ATG): polyclonal lymphocytotoxic serum; preferred based on data
    • rATG: longer t1/2, more durable depletion; worse outcomes in trials
  • Evolution: hATG or CSA mono → hATG + CSA → hATG + CSA + EPAG (current standard)
  • Response rates:
    • hATG/CSA: 60–80% overall at 3mo; hep-AA equally responsive
    • hATG/CSA/EPAG: 87% overall, 39% complete response (vs 80%/30% historical)
    • CR definition: Hb >10, ANC >1 × 10⁹/L, plt >100 × 10⁹/L; mostly by 6mo
  • Eltrombopag (EPAG): TPO agonist; ↑ HSPC expansion; well tolerated (rare rash)
    • 92-pt NIH trial: 87% vs 80% response; replicated in European RCT
    • Originally FDA-approved refractory SAA (40% response)
  • Not improved by: MMF, G-CSF, sirolimus; worse outcomes w/ rATG, alemtuzumab, Cy
  • Toxicity: serum sickness (prevent w/ steroids), infection, rare anaphylaxis
  • Timing: don’t delay for complete genetics (unless IBMFS clear); HLA type/donor search all
  • Duration: 3–6mo response assessment; responders taper CSA

39.2.6.4 Management Algorithm

  • Age ≤40 w/ MSD: HCT 1st-line
  • Age >40 or no MSD: hATG + CSA + EPAG
  • Response at 3–6mo: taper CSA, follow clinically
  • No response:
    • HCT candidate: pursue MSD/MUD/haplo-HCT
    • Not candidate: 2nd IST course, EPAG, anabolic steroids, supportive care
  • Relapse (1/3 of responders): restart oral CSA ± EPAG (often effective)
  • Clonal evolution: 10–20% post-IST → MDS; monosomy 7 poor prognosis, consider HCT

39.2.7 Supportive Issues in SAA

  • Infection prevention: fungal/bacterial major death cause; active fungal ≠ delay Tx
    • VSAA (ANC <0.2): antifungal prophylaxis; AV/PJP role unclear
  • Transfusion: ↑ alloimmunization & TA-GVHD risk
    • Use irradiated, leukodepleted; avoid family members
  • Delayed dx: chronic transfusion HLA alloimmunization → ↓ HCT outcomes

39.3 Pure Red Cell Aplasia (PRCA)

39.3.1 Definition

  • Severe normochromic/normocytic or macrocytic anemia w/ ↓ retics (<10K/μL)
  • WBC & plt counts normal

39.3.2 Classification

  • Congenital: Diamond-Blackfan Anemia (Ch 35)
  • Acquired: immune (primary), 2° (thymoma, T-LGL, immunodeficiency)
    • Also: drug-induced, parvovirus B19, anti-EPO antibodies (rare)

39.3.3 Transient Erythroblastopenia of Childhood (TEC)

  • Healthy infants/young children; self-limited course
  • Unknown trigger; immune suppression of erythropoiesis
  • Spontaneous resolution over several months; supportive care only

39.3.4 Parvovirus B19 Infection

  • Suppresses erythropoiesis in all infected patients
  • Anemia manifests only in immunosuppressed or ↓ RBC survival (SCA, HS)
    • “Aplastic crisis” → often transfusion needed
  • Chronic (immunosuppressed) → PRCA
  • Tx: IVIG for chronic parvo PRCA; antivirals ineffective

39.3.5 ABO-Mismatched HCT

  • Recipient isohemagglutinins (esp anti-A) → ~20% prolonged RBC aplasia
  • Usually improves w/ time; severe anemia → plasma exchange + high-dose ESA effective

39.3.6 Drug-Induced PRCA

  • Many drugs reported; discontinuation may resolve
  • Anti-EPO antibodies (rare; Eprex SQ) → PRCA; antivirals ineffective

39.3.7 Secondary PRCA (Thymoma, T-LGL, CLL)

  • Thymoma: ~5% develop PRCA; ~10–15% PRCA have thymoma
    • Thymectomy response: variable; few complete remissions
  • T-LGL/CLL: PRCA may occur; lymphophenotyping recommended
  • Normal thymus: no benefit from removal

39.3.8 Diagnosis & Workup

  • Clinical: anemia severity–related symptoms; primary PRCA normal exam
    • 2° PRCA: hepatomegaly, splenomegaly, lymphadenopathy
  • Labs:
    • Normochromic/normocytic/macrocytic anemia w/ ↓ retics (<10K/μL)
    • Normal WBC & plt
    • BM biopsy/aspirate: parvo B19 → giant pronormoblasts; T-LGL → lymphocytic infiltrate
  • Additional:
    • Karyotype & FISH → exclude MDS
    • CT chest → evaluate thymoma
    • EPO level, parvo B19 DNA PCR, guided testing

39.3.9 Treatment

  • Immunosuppression 1st-line: 60–70% remission
    • 1st-line: CSA ± prednisone
    • Others: Cy ± prednisone, azathioprine, sirolimus
    • T-cell directed: hATG, alemtuzumab (if T-LGL)
    • Anti-CD20: rituximab (if B-cell lymphoproliferation)
  • Trial duration: 3–6mo per agent; responders treat 3–6mo then slow taper
  • Thymoma: thymectomy + IST (many need IST post-thymectomy)
  • Parvo B19: IVIG (antivirals unhelpful)
  • Refractory: HCT rarely used
  • Relapse (common post-withdrawal): restart effective therapy; long-term if underlying disorder
  • Mortality (nonresponders): infection, iron overload, CV events

39.4 Clinical Pearls

  1. AA diagnosis of exclusion: exclude IBMFS, MDS, PNH before diagnosis
    • Germline testing standard: ~7% undiagnosed IBMFS in transplant cohorts
  2. Age guides Tx: age ≤40 + MSD → HCT (>80%); older/no donor → IST
    • hATG/CSA/EPAG; delays >2–3mo ↓ outcomes
    • Don’t wait for complete genetic testing
  3. PRCA IST: 60–70% remission; CSA ± prednisone 1st-line
    • Thymoma/parvo B19/T-LGL need specific interventions
    • (thymectomy, IVIG, T-cell therapy)