Bone marrow failure syndromes

Overview

• Definition: an intrinsic disorder of the bone marrow with disrupted hematopoietic stem and progenitor cell homeostasis and inadequate production of white cells, red cells, and/or platelets, leading to cytopenias in one or more lineages. May be inherited (germline) or acquired.
• Stem cell biology (perspective): humans have roughly 10,000 to 20,000 true HSCs; each HSC divides only about once every 50 weeks yet is the origin of the ~100 billion new blood cells produced daily. One can live a lifetime with <10% of this HSC pool (as in BMT recipients).
• Distinguish AA vs MDS vs hereditary: use bone marrow cellularity, cytogenetics, molecular profile (clonal hematopoiesis), age, family history, and syndromic features.

Evaluation

• History and physical: infections, drug and toxin exposure, family history, height/weight, congenital anomalies.
• Blood testing: CBC, differential, blood smear review, Hgb F%, LFTs, BUN/Cr, type and screen, DAT, PT/PTT.
• Bone marrow aspirate and biopsy: assess cellularity, dyspoiesis, M:E ratio, megakaryocyte number and morphology, iron stain, reticulin stain (fibrosis), and immunostains (e.g., CD34).
• Cytogenetics: metaphase karyotype plus FISH for chromosomes 5, 7, 8, 13; NGS panel for somatic mutations (increasingly standard); SNP array at some centers.
• Germline testing: skin/buccal fibroblasts for germline genetic testing.
• HLA typing: patient and siblings.
• PNH flow cytometry: CD55/CD59 on RBCs and granulocytes, FLAER on granulocytes.
• Telomere length: age-adjusted lymphocyte telomere length by flow-FISH (6-panel, lymphocyte subsets) if inherited telomere disease suspected; granulocytes may supplement but not replace lymphocyte testing.

Acquired aplastic anemia (AA)

• Pathogenesis: T-cell mediated immune destruction of hematopoietic stem cells.
• Incidence: 2 to 8 cases per million per year, with two peaks (adolescents/young adults ~15 to 25 yr and older adults >60 yr), but can occur at any age.
• Causes / triggers:
  • Idiopathic (most common).
  • Drugs: chloramphenicol, sulfonamides, NSAIDs, anti-thyroid drugs, anti-epileptics (carbamazepine, phenytoin), gold, ticlopidine, clozapine.
  • Toxins: benzene, pesticides, radiation.
  • Viruses: hepatitis (typically seronegative, "post-hepatitis aplastic anemia"), HIV, EBV, parvovirus B19 (transient red cell aplasia, not AA).
  • Pregnancy: rarely.
  • Autoimmune disease: SLE, RA.
  • Pre-leukemic: consider clonal evolution to MDS/AML; PNH overlap.
• Diagnosis: cytopenias plus a bone marrow hypocellular for age (after excluding other causes); the <25%, or 25 to 50% with <30% hematopoietic cells, cutoffs grade severity (Camitta).

• Severe AA (SAA): BM cellularity <25% (or 25 to 50% with <30% residual hematopoietic cells) AND ≥2 of 3: ANC <500/µL, platelets <20K/µL, reticulocytes <60K/µL (or <1% corrected).
• Very severe AA (vSAA): SAA criteria plus ANC <200/µL, worst prognosis without treatment.
• Non-severe (moderate) AA: cytopenias not meeting SAA criteria; less urgent treatment decisions.

• Workup essentials:
  • PNH flow cytometry on RBCs and granulocytes; small clones found in ~50%; significant based on hemolysis, thrombosis, or PNH symptoms rather than size alone; classical hemolytic PNH usually has larger clones (often >50%), while small subclinical clones (AA/PNH overlap) are monitored.
  • Fanconi anemia and telomere disease functional screening must be complete before immunosuppression, especially if young (<40), family history, syndromic features, or refractory disease.
  • Cytogenetics: normal in classic AA; abnormal cytogenetics (esp. -7, +8, complex) suggests MDS.
  • Molecular panel: clonal hematopoiesis is common in AA but does not rule out the diagnosis.

Treatment of acquired aplastic anemia

• HLA-identical sibling donor available: proceed with matched sibling donor transplant. Cure rate ~70 to 90% in patients <30 years.
• No HLA-identical sibling: proceed with immunosuppressive therapy (IST).
  • If IST works and there is no clonal evolution (no progression to MDS): wean immunosuppression and observe.
  • If IST is primary refractory, or there is progression to MDS/AML: proceed with haploidentical or MUD transplant. Relapse after response is usually salvaged first by resuming/increasing CsA +/- eltrombopag or repeat IST; transplant depends on severity, response, age, and donor.
• Stem cell source: bone marrow is preferred over mobilized peripheral blood in AA. Mobilized peripheral blood carries a higher rate of GVHD. Unlike allo-HSCT for malignancy (where GVHD gives a graft-versus-tumor benefit), in AA GVHD is to be avoided at all costs because it is associated with lower OS and lower quality of life.

• Before starting IST: complete Fanconi anemia and telomere disease functional screening; complete HLA typing of patient and siblings (IST is first-line for older or transplant-ineligible patients even if a matched sibling donor exists); goal is to start within 3 to 4 weeks of the diagnostic bone marrow.
• Supportive care during IST: antifungal prophylaxis if ANC consistently <500; HSV prophylaxis x 1 month (some centers); PJP prophylaxis while on cyclosporine (e.g., monthly pentamidine), not a fixed 3 months. G-CSF has no proven benefit other than reduced hospitalization. Use leukoreduced and irradiated blood products, platelets >10K (higher during ATG), Hb >7 to 8. ATG is given through a central venous catheter with a planned ~1-week admission.
• Equine ATG (Atgam): 4 to 8 hour IV infusions x 4 days (hospitalization with close monitoring). Equine ATG is superior to rabbit ATG (thymoglobulin) but is not available in some countries. First-line ORR is higher with horse ATG (68% vs 37% for rabbit). h-ATG/CsA 3-month ORR is 60 to 80%. Rabbit ATG is generally reserved for second-line/salvage when transplant is not an option; a repeat r-ATG plus CsA course rescues ~35% of h-ATG-refractory patients.
• Prednisone: starts with ATG (IV or oral) to prevent serum sickness; it has no role in treating the AA itself. Full dose for 7 to 10 days, then taper over 2 weeks. ATG side effects: severe allergic reactions, anaphylaxis, serum sickness.
• Cyclosporine A (CsA): twice-daily oral, starts with ATG; trough 200 to 350 ng/mL; full-dose duration varies (6 to 12 months, often 12). Side effects: hypertrichosis, gum overgrowth, kidney dysfunction, hypertension, rarely seizures. About 25% of patients remain chronically CsA dependent; relapse in responders is ~35% by 5 years and is often temporally related to CsA discontinuation or dose reduction.
• Eltrombopag: synthetic non-peptide TPO receptor agonist. Upfront with IST (ATG/CsA) for up to 6 months is now standard of care (ORR ~85 to 90%, CR 35 to 40% at 6 months) with clonal evolution ~15% at 4 years (high-risk, myeloid malignancy or chromosome 7: 5.7%), not lower than historical IST alone, though it occurs earlier. Single-agent in refractory disease (Desmond et al. Blood 2014): ~40% ORR, 10 to 12% CR, but 19% clonal evolution (most commonly monosomy 7). Pediatric benefit not demonstrated: adding eltrombopag to IST did not improve response or EFS in children (Groarke BJH 2021), though FDA-approved with standard IST for first-line SAA age ≥2.

• Response (based on count recovery, goal over 6 to 9 months): Complete response = normal counts (some use platelets >100K/µL). Partial response = transfusion independent, ANC >500. Treatment failure = no ANC recovery (ANC <200) by 3 months, or still transfusion dependent by 6 months.
• Repeat BM: mainly to screen for MDS; recheck with any significant decline in counts after initial recovery, and before starting alternative treatment if IST fails.
• Weaning CsA: start 6 to 12 months after initiation; wean by 10% per month or 20 to 25% every 3 months. If counts fall during wean, either resume full-dose CsA or pursue transplant.
• Long-term: CBC every 1 to 3 months for the first year after stopping IST, then decrease toward yearly (indefinite, as late relapse occurs). Check for PNH clones yearly. Clonal evolution to MDS/AML occurs in ~10 to 15% over 10 years.
• Failed first IST: a second IST course (r-ATG plus CsA) rescues only ~30 to 35%; in children, failure-free survival after second IST was ~10% vs ~84% with alternative-donor BMT (Kosaka et al. Blood 2008). Consider alternative donor transplant in young patients: unrelated donor if 9/10 or 10/10 match, or haploidentical with post-transplant cyclophosphamide.
• Transfusion caution: avoid family-member transfusions in patients who may need allo-HSCT (HLA alloimmunization). Use irradiated, CMV-negative, leukoreduced products for HSCT candidates.

PNH overlap and complement inhibition

• Etiology: acquired mutation in the PIGA gene (Xp22.2) causing loss of GPI-anchored cell surface proteins (including CD55 and CD59). Patients typically develop symptoms or need treatment only with clones >30% of blood cells. Up to 50% of SAA patients have PNH clones, most small (<1%). In patients with hemolysis clones tend to increase over time; subclinical clones may increase, remain stable, decrease, or become undetectable after IST.
• Transplant: bone marrow transplant is the only definitive cure. With concurrent AA, transplant outcomes resemble AA without PNH; if PNH progresses and marrow cellularity is restored, more intensive transplant has OS ~70%. Complement inhibition prevents hemolysis and thrombosis but does not affect the course of marrow failure.
• Complement inhibitors: Eculizumab (Soliris, FDA Mar 2007) and ravulizumab (Ultomiris, FDA Dec 2018), anti-C5 mAbs, standard for hemolytic PNH (infusion every 2 to 8 weeks for life). Pegcetacoplan (Empaveli, FDA May 14, 2021), pegylated C3 inhibitor; PEGASUS (Hillmen NEJM 2021) showed superior Hb in patients with persistent anemia on eculizumab. Iptacopan (Fabhalta, FDA Dec 5, 2023), first-in-class oral factor B inhibitor (proximal complement); APPLY-PNH and APPOINT-PNH (NEJM 2024). Danicopan (Voydeya, FDA Mar 29, 2024), oral factor D inhibitor, add-on to ravulizumab/eculizumab for clinically significant extravascular hemolysis (ALPHA, Lee Lancet Haematol 2023). Crovalimab (Piasky, FDA Jun 20, 2024), SC anti-C5 every 4 weeks; COMMODORE-2 (Röth Am J Hematol 2024) non-inferior to eculizumab. Small clones (<10%) without hemolysis do not require treatment. Vaccinate before complement inhibitors: C5 inhibitors (eculizumab, ravulizumab, crovalimab) require meningococcal ACWY plus B; proximal inhibitors (iptacopan, pegcetacoplan, danicopan) also require pneumococcal and Hib.

Pure red cell aplasia (PRCA)

• Definition: severe normocytic, normochromic anemia with reticulocytopenia and absent erythroid precursors in an otherwise normal bone marrow (other lineages preserved). May be congenital or acquired; more frequent in Asians. DDx: MDS, sideroblastic anemia, DBA, transient erythroblastopenia of childhood (TEC).
• Pathogenesis: autoantibodies or T lymphocytes targeting early erythroid precursors. Secondary causes: lymphoproliferative disorder (most common is large granular lymphocyte [LGL] leukemia), autoimmune disease, medication, viral infection (parvovirus B19, especially in immunocompromised, sickle cell, HIV, post-transplant), thymoma (~5 to 10% of thymomas), CLL/lymphoma, pregnancy. ESA-induced anti-EPO antibodies are a rare cause.
• Diagnostic criteria: normochromic, normocytic anemia; absolute reticulocyte count <10,000/µL; normal WBC and platelets (absent concurrent disorders); normocellular marrow with <1% erythroblasts/proerythroblasts and basophilic erythroblasts totaling <5% of nucleated cells.
• Treatment: RBC transfusion plus immunosuppression for primary PRCA. Cyclosporine (± prednisone) is the most effective first-line option (response ~65 to 85%); oral cyclophosphamide plus prednisone is an alternative; second line azathioprine plus prednisone. Refractory: sirolimus (ORR ~75%) or tacrolimus, rituximab (works in CLL-mediated PRCA), IVIG (especially good for B19), daratumumab, antithymocyte globulin, alemtuzumab (anti-CD52), daclizumab (anti-CD25/IL-2Rα, no longer marketed). For secondary PRCA, treat the underlying malignancy; surgery for thymoma; IVIG for parvovirus.
• Post-HSCT PRCA: occurs after major ABO-mismatched transplant when recipient isohemagglutinins interfere with donor erythroid engraftment (major ABO mismatch is not a transplant contraindication). More likely with reduced-intensity/reduced-toxicity conditioning (e.g., fludarabine/busulfan); usually self-limited, often resolving spontaneously or after stopping the calcineurin inhibitor (tacrolimus). Rule out parvovirus B19; for severe/prolonged cases consider rituximab, steroids, plasma exchange, or cyclophosphamide.
• Prognosis: generally good, OS often >10 to 20 years; death is usually from the underlying disorder.

Inherited bone marrow failure syndromes (IBMFS)

• Share an inability to maintain rapidly dividing cells through defective DNA repair, defective telomere/chromosome maintenance, or defective ribosome/protein synthesis.

Related marrow failure / predisposition entities

• Congenital amegakaryocytic thrombocytopenia: >70% due to c-MPL (thrombopoietin receptor) mutations; most develop aplastic anemia by age 5 and need transplant.
• MECOM syndrome: thrombocytopenia with radioulnar synostosis.
• Wiskott-Aldrich syndrome: eczema, microthrombocytopenia, immunodeficiency (low IgM, high IgA and IgE, normal or low IgG, poor polysaccharide responses).
• FPD-AML: RUNX1-associated familial platelet disorder with propensity to myeloid malignancy; single RUNX1 copy loss gives thrombocytopenia with variable penetrance; MDS/AML transformation in 20 to 60%.
• ANKRD26-related thrombocytopenia: autosomal dominant gain of function; moderate thrombocytopenia, ~10% risk of myeloid malignancy (adults).
• Familial AML with mutated CEBPA: autosomal dominant, nearly complete penetrance; a somatic second CEBPA hit drives MDS/AML in adolescents/young adults.
• ETV6-associated familial thrombocytopenia and malignancy: autosomal dominant, often misdiagnosed as ITP, with red cell macrocytosis (usually without anemia); ALL in the young, and MDS/CMML/mixed phenotype in adults.
• Benign constitutional neutropenia: homozygous ACKR1 (Duffy/DARC) SNP, linked to Duffy-negative red cells; partially malaria-protective; benign isolated neutropenia.

High yield (BMF)

• Fanconi anemia = chromosomal breakage with DEB/MMC; FANCD1 = BRCA2; avoid full-dose alkylators/RT at transplant.
• Dyskeratosis congenita = mucocutaneous triad plus short telomeres (flow-FISH <1st percentile); danazol can improve.
• GATA2 = MonoMAC; mycobacterial/viral/fungal infections plus MDS/AML; most common cause of monosomy 7 MDS in AYA.
• SCN (Kostmann): ELANE; AML risk especially with chronic high-dose G-CSF; transplant before MDS/AML develops.
• AA workup: PNH flow plus telomere length plus BMF gene panel; Fanconi/telomere screening before IST.
• AA treatment: matched sibling HSCT first-line for young patients; horse ATG plus CsA plus eltrombopag IST first-line for older patients or no donor; bone marrow (not PBSC) is the preferred graft source.
• PRCA: parvovirus B19 (IVIG), thymoma association, check for LGL leukemia.
• Transfusion: use irradiated, leukoreduced, CMV-negative products in HSCT candidates; avoid family donations.