Bone Marrow Failure

• Bone marrow failure:

  • Disrupted hematopoietic stem and progenitor homeostasis → Inadequate WBC, RBC, Plt

• Pancytopenia differential diagnosis:

  • Autoimmune: HLH, TTP, Lupus, Evan’s syndrome

  • Malignancy: Leukemia, lymphoma, metastatic tumors (myelophthistic), myelofibrosis

  • Infectious

  • Metabolic/Toxins: B12/folate deficiency, excess zinc, storage diseases, alcoholism

  • Bone marrow failure (least common cause)

Acquired Bone Marrow Failure:

• Rapid onset, no family history, usually associated with preceding/inciting event

• Generally treated with immunosuppression

• Causes:

  • Drug reaction

  • Infectious

  • Vitamin/Mineral deficiency

  • Acquired aplastic anemia (AAA)

    • Most commonly idiopathic (80%)

    • Immune-mediated disorder in which cytotoxic T cells attack hematopoietic stem and progenitor cells → profound marrow hypocellularity (usually <30%) and reduction in all hematopoietic lineages.

    • Absence of significant dysplasia and clonal markers in BM

    • Associated with drug, hepatitis, EBV, HIV, parvovirus, pregnancy

    • BM cellularity often <30% and frequently in the range of 5–10%

    • Likely T cell mediated:

      • Cytotoxic activity against marrow cells

      • Cytokines that inhibit blood cell production

    • Associated with development of clonal hematopoesis

      • 13q deletion, PIGA mutations, HLA mutations, CHIP, MDS related mutations (Monosomy 7, complex cytogenetics, DNMT3A, ASXL1, TP53, RUNX1)

    • “Severe” AAA:

      • Bone marrow cellularity < 25% + two of the followings:

        • ANC <500

        • Plt count <20K

        • Retic count <60

      • Treated with matched sibling donor HSCT (if available)

      • If unavailable: trial with immune suppression

        • Equine ATG

        • Prednisone

        • Cyclosporine A

        • Eltrombopag (up to 6 months)

      • If unsuccessful: Haplo/unrelated HSCT

  • Acquired pure red cell aplasia:

    • Normocytic normochromic anemia

    • Very low/zero retic count

    • WBC and plt are normal

    • Normal BM cellularity with few/no erythroid precursors

  • Hypocellular MDS:

    • Hypocellularity

    • Dysplasia in ≥10% of cells in ≥1 lineage (possibly chromosome 5 or 7 abnormalities)

    • Possible increased blasts

    • Clonal cytogenetic/molecular abnormalities

    • Higher risk of progression to AML, poorer prognosis

  • Paroxysmal Nocturnal Hemoglobinuria (PNH):

    • Acquired mutation in PIGA gene leads to loss of GPI anchored cell surface proteins

      • RBCs lacking CD55/CD59 → complement activation and intravascular hemolysis/thrombosis

    • Typically only develop symptoms or requirement treatment with clones >30% of blood cells

      • AA may have small PNH populations ~1%

    • HSCT is only cure

    • More commonly treated with complement inhibitors

      • Important: Needs meningococcal/pneumococcal vaccination before treatment with complement inhibitors

      • Lifelong therapies, expensive

      • Eculizumab:

        • C5 inhibition, blocks intravascular hemolysis

        • IV q1 week loading x4, followed by maintenance q2 week

      • Ravulizumab:

        • C5 inhibition, blocks intravascular hemolysis

        • IV q2 week loading x2, followed by maintenance q8 week

      • Pegcetacoplan:

        • C3 inhibition, blocks intravascular and extravascular hemolysis

        • SQ q2 weeks, patient administered

Inherited Bone Marrow Failure:

• Slow onset, long history, family history of blood disorders

• Usually associated with other developmental abnormalities

• Stem cell transplant is the only cure

• Causes:

  • Diamond-Blackfan Anemia

    • Autosomal dominant (except GATA1 mutated)

    • Ribosomal disorder (gene likely contains RB__, or GATA)

    • Macrocytic anemia

    • Long thumbs (Buzz word), short stature, cardiac/renal abnormalities

    • Associated with osteosarcoma, lower GI malignancies

    • Usually responses to corticosteroids and chronic transfusions

      • HSCT is potentially curative

  • Fanconi Anemia

    • Most common

    • Diagnosed with chromosomal breakage testing

      • Defective DNA repair

    • Associated with >22 genes (mostly autosomal recessive)

    • Buzzwords: short stature, cafe au lait spots, hypoplastic thumbs, microcephaly, hypogonadism/pituitary abnormalities, VACTERL abnormalities, cognitive delays

    • Treatment:

      • HSCT is only curative option

      • Androgens (danazol, oxymetholone)

      • Gene therapy

    • Associated with leukemia, head and neck, skin, CNS and gyn malignancies

  • GATA2 related bone marrow failure

    • Haploinsufficiency (variable phenotype)

    • Associated with transcription factor involved in early hematopoesis

    • Most common cause of monosomy 7 in MDS in young patients

  • SAMD9/SAMD9L syndromes

  • Severe congenital neutropenia

    • Due to misfolded neutrophil elastase (ELANE on 19q)

      • Leads to death of neutrophil precursors (arrest at promyelocyte stage)

    • Delayed cord separation (Buzzword), severe neutropenia (<200), recurrent infections

    • High doses of GCSF can help (long term complications)

  • Schwachman-Diamond Syndrome (SDS)

    • Ribosome disorder (mutation in SBDS)

    • Autosomal recessive 

    • Pancreatic insufficiency, thoracic dystrophy, metaphyseal dysplasia

    • High risk of MDS/AML

      • HSCT with a reduced intensity regimen 

  • Telomere Biopsy Syndromes (dyskeratosis congenita)

    • TTAGGG repeats on telomeres, maintained by telomerase

      • Defective telomerase activity leads to quick aging of cells/telomeres

    • Test: Telomere length analysis

    • Dyskeratotic nails/hair, rash/skin hypertrophy on hands/feet, pulmonary fibrosis, leukoplakia

    • Highly associated with head and neck, skin and anorecal cancers

    • Treatment: Androgens, HSCT

  • WHIM syndrome

    • Warts, Hypogammaglobulinemia, Immunodeficiency, Myelokathexis

    • Treatment: Plerixafor