• Epidemiology: 2–5 cases/106/y; biphasic (major peak in adolescents, 2nd peak in elderly)

• Diagnosis: pancytopenia w/ ↓ retics, BM bx w/ cytogenetics showing hypocellularity

• Etiologies: idiopathic (1⁄2–2⁄3 of cases)

  • stem cell destruction: radiation, chemotherapy, chemicals (eg, benzene) idiosyncratic med rxn (eg, chloramphenicol, NSAIDs, sulfa drugs, gold, carbamazepine, antithyroid)

  • viruses (HHV-6, HIV, EBV, parvovirus B19); also posthepatitis (non A, B, or C)

  • immune disorders (SLE, GVHD post HSCT, thymoma)

  • PNH; Fanconi’s anemia (congenital disorder w/ pancytopenia, macrocytic anemia, ↑ risk of MDS, AML, & SCC of head & neck, and multiple physical anomalies);

  • telomerase (hTERT) mutation

• Treatment and prognosis

  • allogeneic HSCT: for young Pts → ~ 80% long-term survival and significantly ↓ risk of malignant evolution, but has risk of transplant-related morbidity & mortality; if possible avoid transfusions (and alloimmunization) pretransplant

  • immunosuppression (CsA/tacrolimus, ATG): 70–80% respond, with 80–90% 5-y survival in responders; 15–20% 10-y incidence of clonal disorders (mostly MDS, AML, PNH)

  • supportive care: transfusions, antibiotics, possible utility of G-CSF and epo

Definition

• • rare, autosomal dominantly inherited anemia characterized by erythroid aplasia, congenital anomalies, and predisposition to malignancy

  • Diamond-Blackfan anemia is a bone marrow failure syndrome that results from a defect in ribosome biosynthesis, causing red blood cells to be sensitive to death by apoptosis.

Clinical presentation

• • Most patients present in infancy with profound anemia and reticulocytopenia

  • Associated with multiple congenital anomalies

  • Patients have predisposition to malignancy

  • Overall 40-year survival is 75%

Diagnosis

• • DBA is a clinical diagnosis supported by macrocytic anemia and scant RBC precursors in bone marrow

  • Genetic testing is available for 4 known genes associated with DBA, which account for -45% of cases

  • Patients have elevated levels of erythrocyte adenosine deaminase (eADA)

Therapy

• • ~30% Of patients develop spontaneous hematologic remission in 1st decade of life

  • Most patients can be treated with steroids, but some will need chronic transfusions.

  • Glucocorticoids and RBC transfusion are primary treatments

  • Hematopoietic stem cell transplantation is curative and is considered in patients with a human leukocyte antigen-matched sibling or patients who develop acute myeloid leukemia (AML)/myelodysplastic syndrome or aplastic anemia

Definition

• • A hypoplastic or aplastic anemia characterized by pancytopenia with associated skeletal, solid organ, and skin abnormalities

  • Autosomal recessive disorder associated with bone marrow failure, pancytopenia, and increased risk of leukemia

  • Fanconi anemia is a result of defective double-strand DNA repair mechanisms.

Clinic

• • H/P = fatigue, dyspnea on exertion, frequent infections; frequently associated with short stature, abnormal skin pigmentation (café-au-lait spots or hypopigmented areas), horseshoe kidney, and thumb abnormalities

  • Café-au-lait spots, abn of thumbs, hypogonadism, microcephaly

  • Usually pancytopenia beginning at 3–4 years of age, which can lead to bleeding and infection.

  • Other manifestations include hyperpigmentation, skeletal abnormalities (including absent or hypoplastic thumbs), short stature, and other anomalies.

  • Skeletal findings may be subtle in some patients.

  • Congenital anomalies are common, presenting in more than half the patients—these include anomalies of the thumb and radius, as well as of the kidneys, esophagus, genitals, and head and neck.

  • Up to 25% of patients have no physical abnormalities, but since marrow failure usually starts in the first decade of life, these patients should have quarterly blood counts and periodic bone marrow biopsies.

  • In some patients, squamous cell carcinoma may be the initial manifestation of the disease.

Dx

• • Labs = ↓ Hgb, Hct, platelets, and WBCs; ↑ serum α-fetoprotein; BM biopsy shows hypocellularity; chromosome analysis detects multiple strand breakage

  • Bone marrow findings - Aplasia (similar to that seen in acquired aplastic anemia). The bone marrow may be normal if there is no pancytopenia.

  • Diagnostic testing is made by looking at chromosome breakage in peripheral blood lymphocytes cultured with mitomycin C or diepoxybutane.

  • Diagnostic test is confirmation of ↑ chromosomal fragility in the presence of DNA cross-linking agents such as DEB or mitomycin C

  • Telomere length testing is done to look for the diagnosis of dyskeratosis congenita.

Treatment

• • antibiotics, transfusions, bone marrow or hematopoietic stem cell transplantation, hematopoietic growth factors; androgens and corticosteroids can increase bone marrow activity

  • Steroids and androgens (relapse occurs in 50% of patients);

  • G-CSF;

  • bone marrow transplantation

  • Oral androgen treatment with oxymetholone would be an appropriate therapy.

  • Androgen therapy yields an increase in RBCs in approximately half of patients in the first 2 months; it may take up to year for platelet counts and white blood cell counts to rise.

  • Most patients lose the response to androgens as the bone marrow failure progresses.

  • The only curative treatment for bone marrow failure due to Fanconi is hematopoietic stem cell transplant, although patients continue to have an increased risk for other solid tumors such as breast cancer and squamous cell carcinoma.

Prognosis

• • Poor. The median survival age is about 20 years.

  • Complications 5 death in childhood is common from bone marrow failure or leukemia

  • Patients with Fanconi anemia are at increased risk of squamous cell carcinoma as well as aplastic anemia, myelodysplastic syndrome, and AML.