BM Failure Flashcards
(43 cards)
2 kinds of clonal evolution seen in patients with AA
- Hypoplastic MDS
- PNH
Pathopsych of aHUS
Increased activation of the alternative complement pathway because of mutations resulting in loss or functional impairment of complement regulatory proteins, or less frequently, activating mutations in complement proteins themselves →generation of the C5b-C9 MAC → endothelial damage → microvascular thrombotic lesions.
Options for treatment of aHUS
Eculizumab
Plasma Exchange
Required before initiating treatment with Eculizumab
Vaccinations against encapsulated organisms (s.pneumo, H.Flu and particularly against N. meningitides).
Should be done two weeks prior to first dose
What is the mechanism for pulmonary hypertension and erectile dysfunction in PNH?
Intravascular hemolysis → scavenging of NO → vasoconstriction → erectile dysfunction and pulmonary hypertension
Diagnostic test and culprit gene(s): DBA, DC, FA.
- DBA: Elevated RBC adenosine deaminase( ADA)–> RPS19
- DC: Telomer length studies–> DKC1 (x-linked), TERT/TERC (AD) (Others: TINF2, RTEL1)
- FA: Chromosomal breakage studies (on PB, fibroblasts not BM!) cultured with DNA cross linking agent MMC or DEB—> FANCA, FANCC, FANCG
Diagnostic test and culprit gene(s): SDS, SCN (Kostamnn’s syndrome), CAMT, TAR
- SDS: Low pancreatic enzymes (serum trypsinogen, isoamylase, fecal elastase)–> SBDS gene mutations (biallelic)
- SCN: BMBX, arrest of myelopoiesis (promyelocytes are abundant)–>ELANE, HAX1
- CAMT: BMBX, decreased or absent megakaryocytes–> c-MPL (biallelic), encodes TPO receptor
- TAR: BMBX, decreased or absent megakaryocytes–> RBM8A (biallelic)
Inheritance pattern of Congenital BMT syndromes:
DBA, DC, FA, SDS, SCN (Kostamann’s syndrome), CAMT, TAR.
DBA: AD (can be x-linked)
DC: X-linked (can be AD or AR)
FA: AR (can be x-linked or AD)
SDS: AR
SCN: AD (can be AR)
CAMT: AR
TAR: AR
Fanc-shanc-CAMtar=AR
3 germ-line mutations which predisposition to MDS/AML and thrombocytopenia.
runx1, etv6, Ankrd26
Diagnostic criteria of DBA.
The diagnosis of classic DBA is made if all of the following diagnostic criteria are met:
●Age <1 year
●Macrocytic anemia with no other significant cytopenias
●Reticulocytopenia
●Normal marrow cellularity with a paucity of erythroid precursors
3 physical characteristics are traditionally seen with dyskeratosis congenita?
Oral leukoplakia
Nail dystrophy
Abnormal skin pigmentation
Hepatic fibrosis
Pulmonary fibrosis
Esophageal and urethral strictures
Grey Hair
Retinopathy
Hypogonadism
Chronic alcoholic, 4 reasons for anemia
1.Direct toxicity to marrow by alcohol
2. Suppression of EPO production by alcohol
3. Blood loss from variceal/ulcer bleeding
4. B12/Folate/Copper/B6 deficiency secondary to malnutrition
5. Anemia of liver disease
6. Zieve’s syndrome
Risk factors for chemotherapy-associated neutropenia (solid organ) and its complications
Age >65 years
Previous chemotherapy or radiation therapy
Bone marrow involvement of tumor
Preexisting neutropenia, infections, open wounds, or recent surgery
Poor performance status
Decreased renal function
Decreased liver function, particularly increased bilirubin level
What is the role for G-CSF in febrile neutropenia?
-accelerated the time to neutrophil recovery
- shortened hospital stay
-but did not affect OS
Can consider only if:
-expected to have prolonged (> 10 days) and profound neutropenia (< 0.1 × 109/L);
- > 65 years old with pneumonia, hypotension/sepsis, or invasive fungal infections
What is the role for G-CSF in AML and ALL?
Induction:
1. AML- may shorten the duration but does not decr FN, infxns or hospital duration.
Consolidation:
1. AML- dec duration of severe neutropenia, and infxs requiring ABx
ALL: dec duration of neutropenia but no change in # of infxns, hospitalizations, or improve OS.
Anemia of aging. What is the prevalence and what is it an independent RF for?
11% of men and 10% of women over age 65 years, 30% >80.
Increased risk of:
-cognitive decline
-decreased bone density
-decreased muscle strength
-poor physical performance
-increased hospitalization
-morbidity
-mortality
Response rate for triple therapy (Horse ATG + CycA +EPAG) in AA. What is the starting dose? In what pt population would you NOT add EPAG?
90% RR to triple therapy in SAA. 50% with have CR. 2 year OS 97%. 10 year survival=90% (response time usually 12 weeks but up to 6 mos!)
Untreated, SAA has a one-year mortality of >70%
Dose: eltrombopeg 150MG daily on Day 1
Relative CI: Pt with clonal abnormality for fear that it will stimulate clone expansion.
Hematologic criteria for severe AA? Very severe AA?
Bone marrow cellularity <25 percent (or 25 to 50 percent if <30 percent of residual cells are hematopoietic)
2/3 of:
Severe:
ANC<0.5
Retic<20
Plt <20
Very severe:
As above BUT ANC<0.2
*++ debate about retic numbers (20-60) and marrow cellularity among different sources.
3 predictors of response to IST in AA?
- Presence of a PNH clone
- Favorable mutations: BCOR, BCORL1, PIGA (PNH mutation- better than PNH clone)
- Better counts at presentation: Absolute retic count (ARC) >25, Absolute lymph count (ALC) >1
- Age < 60
- Male better
- Time from diagnosis to treatment <1 month
What IBMF syndromes predispose to solid tumors?
FA (head/neck: HNSCC)
DKC (HNSCC)
DBA (sarcomas, colon, GU in females)
5 clinical features of Fanconi’s anemia.
- Short stature
- Triangle facies
- Cafe au lait spots
- Increased Hg F
- Microcephaly
- Radial ray defects (thumb abnormalities)
Why is it important to rule out Fanconi’s anemia as a cause of bone marrow failure in a pt with AML or MDS prior to allo-SCT?
Exquisite sensitivity of patients with FA to the DNA damaging effects of chemotherapy and radiation. They need a modified conditioning regime.
*note SCT will only correct BM failure but does not improve (and actually worsening) risk of developing solid organ neoplasm. Need frequent malignancy monitoring.
What is the triad of integument findings in dyskeratosis congenita? What are 3 other clinical features?
- Oral leukoplakia
- Abnormal skin pigmentation
- Nail dystrophy
Others:
-pulmonary fibrosis
-cirrhoiss
-hepatopulmonary syndrome
-head and neck and other solid organ neoplasms
What is Hoyeraal-Hreidarsson syndrome?
severe multisystem telomere biology disorder, characterized by growth retardation of prenatal onset, microcephaly, cerebellar hypoplasia, BM failure, and immunodeficiency.