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)
7 yo girl presents with pancytopenia and <5% blasts.
a) Name 3 reasons why it is important to differentiate idiopathic aplastic anemia from IBMFS.
b) List 4 things on history that would make you suspicious of an IBMFS.
c) List 3 IBMFS that would be on your differential and name the investigations you would do for each
a)
- Initial management is different – patients with IBMFS are managed by supportive care +/- HSCT when necessary, patients with idiopathic aplastic anemia may respond to immunosuppressive therapy with cyclosporine + ATG + steroids – response rates ~ 50-75% before making the decision to go to HSCT
o eltrombopag is not currently used in children for IST – limited evidence – used in adults
- If the patient goes to HSCT – certain regimens are associated with toxicity in patients with IBMFS (FA, DKC, SDS)
o Need reduced-intensity transplant regimen to avoid excessive morbidity and mortality
- Children with IBMFS who go to HSCT remain at increased risk of solid tumours – require monitoring for early detection
- Need to rule out IBMFS in any potential sibling donors
- Genetic counselling for family / family planning / carrier testing
b)
- Poor growth (IUGR, low birth weight, short stature, FTT etc)
- Poor nail or hair growth
- Dental anomalies, oral leukoplakia (can be mistaken for thrush)
- Symptoms of fat malabsorption – steatorrhea / fatty food intolerance
o Also: vomiting, poor appetite, abdo pain
- Hx of hepatomegaly / eczema / transaminitis in infancy – features of SDS
- Cardiac anomalies
- Osteopenia – pathologic fractures
- Endocrinopathies – hypogonadism (delayed puberty, amenorrhea)
- Suspicious family hx of cancer predisposition (cancers at young ages, certain types of cancer)
o Autosomal dominant family hx of cancer can be seen in subtypes of DKC
- Excessive toxicity from chemotherapy or radiation therapy
- Family hx of unexplained cytopenias, aplastic anemia
- Pulmonary fibrosis (in family members) – feature of DKC
- Family hx of unexplained fetal loss / congenital anomalies
c)
(ASH review, Old and new tools in the clinical diagnosis of IBMFS, West, 2017)
General investigations in patients who you suspect an IBMFS
- CBC – specifically looking for MCV
- Hemoglobin analysis – HbF may be elevated
- Bone marrow – to assess cellularity, cytogenetics, dysplasia
Fanconi anemia
- Chromosomal breakage in response to MMC or DEB
- (other chromosomal breakage syndromes – ataxia telangiectasia, bloom syndrome – can distinguish through MMC and DEB – may not be able to distinguish Nijmegan breakage syndrome)
- performed on phytohemagglutinin (PHA) stimulated peripheral blood lymphocytes
- if blood test is normal – may be related to reversion of fanconi anemia gene mutation in a somatic cell, resulting in a falsely negative result – can test skin fibroblasts if highly suspicious
- Genetics: FA usually has autosomal recessive inheritance therefore need to find two mutations, most common FANCA
DKC (aka TBDs – telomere biology disorders)
- decreased lymphocyte telomere lengths (telomere lengths may be artificially low in granulocytes) – usually below the 1st percentile for age (highly sensitive and specific)
- Genetics: ACD, CTC1, DKC1, NAF1, NHP2, NOP10, PARN, POT1, RTEL1, TERC, TERT
- TERT – most common cause of adult onset pulmonary fibrosis
SDS
- pancreatic isoamylase / trypsinogen, fat soluble vitamin levels
- most common genetics: SBDS (AR)
SCN
- bone marrow demonstrates promyelocyte maturation arrest
- most common genetics: ELANE (others: HAX1 – Kostmann’s neutropenia)
Fanconi Anemia – kid needs BMT, brother is a complete HLA match but has café-au-lait spots and short stature and his chromosome breakage is negative.
a) What might explain why you’d be suspicious of the negative chromosome breakage?
b) Two specific modifications/considerations to conditioning regimen in the case of FA?
c) What specific problem with chronic GvHD are kids with FA at risk for?
a) high degree of suspicion given that sibling is known to have FA and first degree relative has dysmorphic features associated with FA
chromosomal breakage testing can be negative in the blood due to somatic reversion (some patients with FA can demonstrate normal levels of chromosomal breakage in DEB testing of peripheral blood) - need to test skin fibroblasts if high suspicion.
This happens when there is a somatic hematopoietic reversion event - a progenitor cell has corrected the defect on 1 allele resulting in hematopoietic mosaicism
b)
children with FA are uniquely sensitive to conditioning agents - need reduced intensity conditioning
can be achieved by minimizing radiation (or eliminating completely), low-dose cyclophosphamide, ATG (associated with less GVHD)
Blood 2013: survival benefit to using fludarabine-containing regimen (better engraftment, lower rate of aGVHD and better OS) without irradiation
c)
children with chronic GVHD are at increased risk of developing SMNs (most commonly ST)
-for patients who survive > 1 year post HSCT, there is a cumulative incidence SMNs of 21% at 15 years post (34% at 20 years post) - mostly solid tumours (89%)
-age > 10 yrs, peripheral blood source, transplant at later stages of disease, chronic GVHD - independent predictors of developing SMN
-use of irradiation and donor type did not correlate with SMNs (Blood 2013)
Define what is severe aplastic anemia?
Define very severe Aplastic Anemia.
Severe aplastic anemia (SAA) is defined by:
- Bone marrow cellularity of less than 25%.
- At least two of the following cytopenias:
>granulocyte count <500/mm3 (<200 mm3 defines very SAA)
>platelet count < 20,000/mm3
>reticulocyte count <20,000/mm3
Non-SAA occurs when the above criteria are not met. There is little consensus on distinguishing between mild
and moderate aplastic anemia.
VSAA: The above with ANC <200/mm3
List two age peaks in aplastic anemia.
Epidemiological studies have shown a bimodal age distribution with an early peak at 15–25 years and a later peak at ≥60 years
List baseline investigations for patients with pancytopenia.
CBC Bone marrow aspirate and biopsy Serum B12, RBC folate Anti-dsDNA, ANA, DAT, rheumatoid factor Viral serology +/- PCR: Hep A/B/C, EBV, CMV, parvo, VZV, HIV LFTs to exclude hepatitis TB test Cytogenetics Mutational analysis Chromosomal breakage for Fanconi anemia Telomere length for DKC Flow cytometry for PNH Imaging: X-rays: chest, skeletal U/S: renal, cardiac, abdo for congenital causes
What is pathophysiology of idiopathic aplastic anemia?
Immune mediated via IFN-gamma, TNF, Fas ligand activation
Secreted by T lymphocytes
Suppress mitotic cycle of HSC or direct cell killing/apoptosis
List 5 components to supportive care in Acquired aplastic anemia
Minimize transfusions:
complete blood type grouping prior to any transfusions
Leukoreduction or CMV-neg products
Irradiated products if prev received IST
Monitoring for iron overload in chronic RBC transfusions
Menses suppression
Avoid platelet antagonists
Caution with IM injections
Consider anti-fibrinolytic agents, ex. TXA/Amicar, for mucosal bleeding
Infections:
Good dental care
Avoid hospitals unless required
Rectal area: monitoring for fissures, no rectal temps
Culture from possible sources if febrile
F&N protocol if neutropenic
Consider fungal infections if still febrile 4-7d while in broad spect ABx
When is treatment indicated for Acquired Aplastic Anemia
For severe aplastic anemia/SAA; otherwise supportive care only
When is HSCT indicated? What type of conditioning regimen.
First-line for SAA with MSD (95% engraft, 90% 2-yr OS)
-Cy+ATG+CSA for GVHD
SAA with MUD 10/10, or 8/8 in 2-3months (outcomes non-inferior to MSD)
SAA refractory/relapse to IST with MUD 10/10 or 8/8 in 1st year
Conditioning:
-Flu+Cy+Campath (Alemtuzumab, anti-CD52 Ab - expressed on normal and malignant B and T-cells, NK, monos, macrophage)
