MDS / Marrow failure Flashcards
List common side effects of ATG and CSA
ATG: Anaphylaxis Thrombocytopenia, leukopenia H/A Myalgia Chills, fever Chemical phlebitis Itchhing, erythema Serum sickness 7-10days after; Tx with increasing doses of steroid
CSA: Renal dysfunction: dose reduce if 30% rise in Cr Tremor Hirsuitism HTN Gingival hyperplasia
What is the risk associated with IST for aplastic anemia?
Long-term risks of relapse
CSA dependence
Clonal evolution (10-40% of those Tx with IST)
What are salvage therapy options after failed IST for aplastic anemia
MUD HSCT
If not available: consider 2nd course of IST: options include…
Switching to rabbit ATG - some evidence of benefit
Switching to tacro from CSA - no proof of benefit
High-dose CPM w/o transplant controversial
Eltrombopag added to hATG+CSA
What is pathophysiology of PNH and clinical features?
Somatic mutation in PIG-A gene in HSC leading to block in biosynthesis of GPI anchor, which is required for several surface proteins.
Hematopoetic stem cells are then more prone to complement-mediated destruction
Absent CD55, CD59 C’ regulatory proteins
Higher risk of thrombosis:
C’ deposition on plt - procoagulant
Impaired fibrinolysis from lack of GPI-linked urokinase plasminogen activator - impaired fibrinolysis
Three key manifestations:
Paroxysmal intravascular hemolysis - hemoglobinuria, abdo/back pain; episodes usually every few weeks
BMF: macrocytosis, pancytopenia, severe AA)
Venous thrombosis - leading cause of death
Fanconi anemia - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence: most common IBMFS - 1/200,000; heterozygote freq of 1/181 North America
Pathophysiology: defective DNA damage response and genomic instability
Genetics: due to mutations in the FANC- complementation genes; FANCA, FANCC, FANCG represent 90% of cases; inherited as AR issue; X-linked in <1% of cases (FANCB)
Clinical features: pancytopenia short stature cafe au lait macules, hypopig/hyperpig spots male hypogenitalism microcephaly microopthalmia renal, cardiac anomalies 800% more likely to develop L&L (AML, MDS), and more with solid tumors (H&N SCC, vulvar cancer, uterine cervical cancer)
Diagnosis:
- Screening: increased chromosomal breakage in T-lymphocytes after DEB (more common) or mitomycin C exposure; or flow cytometry after alkylating agent Tx for G2/M phase arrest; use cultured skin fibroblasts with mosaicism on DEB testing
- Definitive: complementation group analysis, targeted seq, copy number analysis for FANC genes
Schwachman-Diamond syndrome - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence:
Estimated 1/77,000 (accounting for 14% of IBMFS)
Pathophysiology
Abnormal ribosomal assembly and inadequate maintenance of the stromal microenvironment
Genetics
Mutation in SDSB gene, AR inheritance (homozygote or compound heterozygote)
Clinical features BMF, especially neutropenia Exocrine pancreatic deficiency Metaphyseal dysplasia Mental retardation Cardiomyopathy Immune dysfunction; recurrent infections Transformation to MDS/AL in 18-36%
Diagnosis
Clinical: Cytopenia of any lineage (2x over 2 months) + exocrine pancreatic deficiency (based on fecal elastase, serum trypsinogen (for age <3y), serum isoamylase (age >=3y), serum lipase
Genetics (confirmatory only): biallelic inactivation of SDSB
Dyskeratosis Congenita - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence
1/1,000,000
Pathophysiology
Deficient telomerase activity leading to very short telomeres
Genetics DKC1 (X-linked), and other genes involved in telomere maintenance (AD or AR inheiritance)
Clinical features
Classic triad of ectodermal dysplasia:
Abn skin pigmentation of upper chest and neck
Dysplastic nails
Leukoplakia of oral mucous membranes
Somatic features: esophageal strictures lacrimal duct destruction severe dental or periodontal disease recurrent infections due to immune deficiency enteropathy/enterocolitis short stature hypogonadism urethral strictures cognitive developmental impairment
Later in life (2nd decade +): pul fibrosis, liver disease, vascular malformations, osteoporosis, neuropsyciatric, premature graying of hair
Increased risk of cancers, similar to Fanconi anemia but lower frequencies and older patients
Severe forms have neurological defects: Hoyeraal-Hreidarsson (HH) syndrome: IUGR, dev delay, severe immune deficiency, BMF, cerebellar hypoplasia Revesz syndrome (RS).
Late pulmonary fibrosis in adult life (if survive)
Diagnosis
Clinical:
All three Sx of triad
⅓ triad Sx + BMF + 2 somatic features
Lab:
telomere length analysis: multicolour flow FISH (average telomere length <1st %tile)
confirmatory sequencing in pt and relatives (for donor eligibility)
Diamond-Blackfan Anemia - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence:
5-10 per million live births
Pathophysiology: Defective ribosome biosynthesis (small or large subunit-associated ribosomal protein haploinsufficiency) causing erythroid progenitors and precursors to be highly sensitive to death by apoptosis
Genetics:
- RPS19 accounts for 20-25% Auto Dominant (11 genes identified)
- X-linked recessive (GATA1), or possibly AR as well
Features:
- PLT and WBC normal, thrombocytosis rare, thrombocytopenia and/or neutropenia may occur.
- craniofacial abN in 50%
- hand abN, bifid thumb
- 39% GU
- 30% cardiac
- Low birth weight occurs in approximately 10%
- Cancer predisposition (GI and colorectal, osteo, MDS/AML)
Diagnosis:
Diagnostic criteria:
- Age <1y
- Macrocytic normochromic anemia
- Reticulocytopenia
- Paucity of erythroid precursors in marrow.
Patients are diagnosed with “’classic DBA” if they meet all the diagnostic criteria (age < 1 yr, macrocytic anemia, reticulocytopenia, paucity of BM erythroid precursors)
Patients are diagnosed with “non-classic DBA / probable diagnosis” if they meet:
o 3 diagnostic criteria + one major OR two minor supporting criteria, OR
o 2 diagnostic criteria + two major OR three minor supporting criteria
Major: - Positive FHx Minor: - Elevated red cell ADA - Elevated HbF - Macrocytosis - Congenital abnormalities
Definitive (not essential):
- Pathogenic mutations
Pearson Syndrome - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence: “rare”
Pathophysiology:
Impaired production of heme resulting from defects in these
enzymes results in mitochondrial iron accumulation, damage to the mitochondrial machinery, and formation of ring sideroblasts.
Genetics:
Mitochondrial DNA deletions ranging from 2-10 kilobases in size (pathognomonic, maternal inheritance)
Features: - severe anemia - neutropenia - thrombocytopenia - exocrine pancreatic dysfunction (fat malabsorption) - fatal in infancy - if survive beyond infancy, develop signs and symptoms of Kearns-Sayre Syndrome(neurodegenerative disease)
Dx:
Marrow: vacuolated precursors/ringed sideroblasts
Congenital Amegakaryocytic Thrombocytopenia - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence: “Rare”
Pathophys: Mutations in myeloproliferative leukemia virus oncogene MPL, which encodes the thrombopoietin receptor, c-MPL, and is an essential regulator of megakaryocytopoiesis and PLT production
Genetics: AR; Thrombopoietin receptor at 1p34
Features:
- Thrombocytopenia at birth
- Usually present with bleeding into the skin, mucous membranes, or GI tract
- Macrocytic RBCs, normal sized PLTs
- Increased HbF
- High risk of MDS → AML
- Pancytopenia develops later in childhood
- NO skeletal abN (differentiates it from TAR)
Diagnosis: Decreased or absent bone marrow megakaryocytes
Mutation of MPL gene, but not necessary for CAMT diagnosis
Thrombocytopenia Absent Radii (TAR) syndrome - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence: “rare”
Pathophys: Thrombocytopenia caused by dysmegakaryocytopoiesis with differentiation blockade at the stage of an early megakaryocyte precursor
Genetics: AR
RBM8A gene mutations (RNA-binding motif protein 8A) at 1q21.1
Features:
- Severe thrombocytopenia at birth (PLT<10-30)
- Bilateral absence of radii with PRESENCE of thumbs
- Leukemoid reaction, hypereosinophilia
- Micrognathia, brachycephaly, hypertelorism, webbed neck, hypogonadism, limb abN, congenital heart disease (ASD or TOF)
- Significant mortality in neonatal period due to intracranial hemorrhage
Dx:
Bone marrow shows normal erythroid and myeloid precursors with absent/decreased megakaryocyte
Paroxysmal Nocturnal Hemoglobinuria - relative incidence, pathophysiology and genetics, clinical features, and diagnostic studies?
Incidence: 1 to 10 cases per million
Mostly a disease of adults
Males = females
Pathophys: Clonal stem cell disorder, PIG-A functions in glycosylphosphatidylinositol (GPI) anchor biosynthesis, PNH cells deficient in GPI anchored proteins CD55/59 leaving cells at risk for complement-mediated lysis
Genetics: Acquired somatic mutations in PIG-A gene (Xp22.1)
Features: Hemolysis via alternative pathway of complement (intra and extravascular), hemoglobinuria classically in the morning, thrombosis (venous mesenteric) is leading cause of death
Dx: Flow cytometry to quantitate % of GPI deficient anchored protein on granulocytes and other cell lineages
List factors that distinguish DBA and TEC
Characteristics: TEC: Acquired/transient Slightly older children (> 6 months, generally between 1-4 yrs of age) Hemoglobin 30-90 DBA: Congenital Young children (usually < 1 yr) Usually more severe anemia than TEC (hemoglobin 20-60)
Features:
Both can have anemia, reticulocytopenia
MCV:
TEC: Usually normal
DBA: May be elevated
ADA:
TEC: Normal
DBA: May be elevated
Etiology:
TEC: Unknown ? viral illness (in 50% of cases child has a virus in the preceding 3 months)
DBA: Genetic – mutations in RPS or RPL (ribosomopathy)
Hemoglobin F:
TEC: Normal
DBA: May be elevated
Natural hx:
TEC: Full spontaneous recovery
DBA: Prolonged transfusion support or steroid tx
How is the management unique in DBA? When is HSCT indicated?
- Supportive RBC transfusions – 20-30% recover spontaneously after supportive care
- After ~ 6-12 months of age, trial of corticosteroids is given, has 60-70% response rate
- Transplant indicated for non-responders: transfusion dependent, require chelation therapy
- IBMTR review of patients with DBA who underwent HSCT (61 patients, median age at transplant of 7 yrs) – survival at 3 yrs ~ 63%
- Optimal time of transplant – after they become refractory to steroids, but before excessive RBC transfusion (> 20-25) – high ferritin associated with poor post HSCT outcome
What is the prognosis for IBMFS in general and in specific IMFS?
In general:
- Outcomes of IBMFS are variable, depending upon the risk of transformation to MDS/AML and if they present before this stage – cumulative risk of transformation to MDS by 18 yrs of age is 37% for all children with IBMFS (see Cada et al Hematologica, 2015)
