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Hematology > BM Failure > Flashcards

BM Failure Flashcards

1
Q

2 kinds of clonal evolution seen in patients with AA

A
  1. Hypoplastic MDS
  2. PNH
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2
Q

Pathopsych of aHUS

A

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.

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3
Q

Options for treatment of aHUS

A

Eculizumab
Plasma Exchange

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4
Q

Required before initiating treatment with Eculizumab

A

Vaccinations against encapsulated organisms (s.pneumo, H.Flu and particularly against N. meningitides).
Should be done two weeks prior to first dose

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5
Q

What is the mechanism for pulmonary hypertension and erectile dysfunction in PNH?

A

Intravascular hemolysis → scavenging of NO → vasoconstriction → erectile dysfunction and pulmonary hypertension

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6
Q

Diagnostic test and culprit gene(s): DBA, DC, FA.

A
  1. DBA: Elevated RBC adenosine deaminase( ADA)–> RPS19
  2. DC: Telomer length studies–> DKC1 (x-linked), TERT/TERC (AD) (Others: TINF2, RTEL1)
  3. FA: Chromosomal breakage studies (on PB, fibroblasts not BM!) cultured with DNA cross linking agent MMC or DEB—> FANCA, FANCC, FANCG
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7
Q

Diagnostic test and culprit gene(s): SDS, SCN (Kostamnn’s syndrome), CAMT, TAR

A
  1. SDS: Low pancreatic enzymes (serum trypsinogen, isoamylase, fecal elastase)–> SBDS gene mutations (biallelic)
  2. SCN: BMBX, arrest of myelopoiesis (promyelocytes are abundant)–>ELANE, HAX1
  3. CAMT: BMBX, decreased or absent megakaryocytes–> c-MPL (biallelic), encodes TPO receptor
  4. TAR: BMBX, decreased or absent megakaryocytes–> RBM8A (biallelic)
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8
Q

Inheritance pattern of Congenital BMT syndromes:
DBA, DC, FA, SDS, SCN (Kostamann’s syndrome), CAMT, TAR.

A

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

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9
Q

3 germ-line mutations which predisposition to MDS/AML and thrombocytopenia.

A

runx1, etv6, Ankrd26

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10
Q

Diagnostic criteria of DBA.

A

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

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11
Q

3 physical characteristics are traditionally seen with dyskeratosis congenita?

A

Oral leukoplakia
Nail dystrophy
Abnormal skin pigmentation
Hepatic fibrosis
Pulmonary fibrosis
Esophageal and urethral strictures
Grey Hair
Retinopathy
Hypogonadism

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12
Q

Chronic alcoholic, 4 reasons for anemia

A

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

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13
Q

Risk factors for chemotherapy-associated neutropenia (solid organ) and its complications

A

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

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14
Q

What is the role for G-CSF in febrile neutropenia?

A

-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

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15
Q

What is the role for G-CSF in AML and ALL?

A

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.

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16
Q

Anemia of aging. What is the prevalence and what is it an independent RF for?

A

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

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17
Q

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?

A

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.

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18
Q

Hematologic criteria for severe AA? Very severe AA?

A

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.

19
Q

3 predictors of response to IST in AA?

A
  1. Presence of a PNH clone
  2. Favorable mutations: BCOR, BCORL1, PIGA (PNH mutation- better than PNH clone)
  3. Better counts at presentation: Absolute retic count (ARC) >25, Absolute lymph count (ALC) >1
  4. Age < 60
  5. Male better
  6. Time from diagnosis to treatment <1 month
20
Q

What IBMF syndromes predispose to solid tumors?

A

FA (head/neck: HNSCC)
DKC (HNSCC)
DBA (sarcomas, colon, GU in females)

21
Q

5 clinical features of Fanconi’s anemia.

A
  1. Short stature
  2. Triangle facies
  3. Cafe au lait spots
  4. Increased Hg F
  5. Microcephaly
  6. Radial ray defects (thumb abnormalities)
22
Q

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?

A

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.

23
Q

What is the triad of integument findings in dyskeratosis congenita? What are 3 other clinical features?

A
  1. Oral leukoplakia
  2. Abnormal skin pigmentation
  3. Nail dystrophy

Others:
-pulmonary fibrosis
-cirrhoiss
-hepatopulmonary syndrome
-head and neck and other solid organ neoplasms

24
Q

What is Hoyeraal-­Hreidarsson syndrome?

A

severe multisystem telomere biology disorder, characterized by growth retardation of prenatal onset, micro­cephaly, cerebellar hypoplasia, BM failure, and immunodefi­ciency.

25
Q

What are 2 treatments for DC? Which one of these treatments should not be used with G-CSF because of increased risk of splenic rupture.

A
  1. allo HSCT with NMA
  2. Androgens (Danazol and oxymetholone)- should not be used with G-CSF!
  3. Transfusion support
26
Q

What cell organelle is primarily affected in SDS?

A

Ribosomes (biallelic mutations in the SBDS gene affect ribosome biogenesis)

27
Q

How do you treat DBA?

A
  1. Steroids! (but avoid in infants <1 yr due to side effects)
  2. pRBC (monitor for iron OL)
  3. ~60% spontaneously remit, 40% will be pRBC dependent
  4. In those who do not remit–>allo SCT (but ideally before iron OL develops)
28
Q

What are 3 clinical features and 2 morphologic features of congenital dyserythropoietic anemia type 1 (CDA1)? (note: the gene affected is CDAN1)

A

Clinical
1. Mod hemolytic anemia (Hg 90-100), macrocytosis, reticulocytosis
2. Skeletal abnormalities (ineffective erythropoiesis)
3. Iron overload (in the absence of Tx)
4. Splenomegaly

Morphologic
1. binucleated erythroblasts
2.erythroid hyperplasia
3.internuclear chromatin bridging

Responds very well to IFN-alpha, but usually does not require Tx support b/e anemia is mild!

29
Q

CDA II is more common than CDI and can be misdiagnosed as _____. It is caused by biallelic mutations in_____.

A

-misdiagnosed as hereditary spherocytosis
-multinucleated giant erythroblasts, low reticulocyte
-biallelic mutations in SEC23B.

30
Q

SCN (Kostmann’s syndrome) predisposes to AML with what somatic mutation?

A

CSF3R

31
Q

What is WHIM syndrome?

A

warts (HPV)
hypogammaglobulinemia
infections (neutropenia)
myelokathexis (BM with hypercellularity and increased numbers of neutrophils in BM, despite low peripheral ANc)

heterozygous mutations of the CXCR4 gene! Can Tx with plerixafor.

32
Q

What is the treatment and prognosis of TAR?

A

Tx-plt transfusions (plt usually <50), may bleed as infants but usually improves by 1 yr

Prognosis- excellent, no clear increased risk of heme malignancies

33
Q

CAMT is caused by biallelic mutations in c-MPL which encodes TPO receptor. In pts with CAMT, is TPO high or low?

A

High!

*can progress to AA, AML or MDS.

34
Q

What are 5 common culprit drugs associated with neutropenia?

A
  1. Cocaine
  2. Heroin
  3. Rituximab
  4. Dapsone
  5. PTU (propylthiouracil)
  6. MMA (methimazole)
  7. Vancomycin
  8. Penicillin G (and cephalosporins)
  9. sulfasalazine
  10. Carbamazapine
  11. Valproic Acid

Others: carbimazole, clozapine, dipyrone, procainamide, ticlopidine.

35
Q

What is the pathogenesis of aplastic anemia?

A

AA is thought to be initiated by recognition and destruction of HSCs by cytotoxic T lymphocytes, which recognize some unknown antigen present on HSCs via their HLA class I molecule.

36
Q

T-LGL is most commonly a/w which autoimmune condition? What are 2 positive CD markers in T-LGL vs. NK LGL? What mutational testing should be sent?

A
  1. RA (can also be seen in lupus)
  2. T-cell (CD 3+, CD 57+), NK (CD 3-, CD 56+). Send TCR gene-rearrangement studies!
  3. STAT 3 mutation analysis
37
Q

How is horse and rabbit ATG made?

A

-human T cells are delivered to a horse or rabbit.
-the immunized animal then produces Abs against antigens expressed on the surface of a T cell
-These are subsequently are harvested/purified.

–>polyclonal horse or rabbit serum has lymphocytotoxic properties–> lymphocyte depletion

(rabbit is more lympho-depleting and longer half life)

38
Q

A pt previously treated for AA has transformed to MDS (risk is 20% in 20yrs). What are the most common cytogenetics findings and their effect on prognosis?

A

monosomy 7 (poor prognosis) or a trisomy 8 (usually respond to IST).

39
Q

Pt develops AA in pregnancy. What is the remission rate following delivery or abortion? What is one treatment option in pregnancy?

A
  1. 25-30% remission when baby is out.
  2. CycA, steroids ok in pregnancy (ATG has been used but less well studied).
40
Q

What are two inherited bone marrow failure disorders which will not progress to aplastic anemia?

A
  1. CDAs (never)
  2. TAR (rare)
  3. Cyclic Neutropenia or severe congenital neutropenia
  4. Wiskott-Aldrich Syndrome
41
Q

What is Myelokathexis, how is it inherited and what is the gene that is affected? What syndrome is a part of?

A

Myelokathexis, (kathexis = retention). Gain of function mutation in CXCR4 (AD inheritance) or loss of function mutation in CXCR2 (AR inheritence) that causes mature neutrophils to be “locked” in the bone marrow.

Part of WHIM syndrome (Warts, Hypogammaglobulinemia, Infections, Myelokathexis)

-Clinical features vary and may include severe neutropenia, lymphopenia but BM is hypercellular, suggesting impaired release of neutrophils from the bone marrow .
-Distinct morphology- hypersegmented cells with abnormally long chromatin filaments connecting the nuclear lobes, have an unusual shape, and contain degenerative pyknotic nuclei and cytoplasmic vacuoles (ie, myelokathexis)

-Tx G-CSF and plerixafor can be used to release neutrophils into periphery.

42
Q

What is the gene associated with cyclic neutropenia?

A

ELANE (ELA2) mutations found in essentially 100% of cyclic neutropenia
NOT associated with an increased risk of AML

43
Q

Primary auto-immune neutropenia-age at onset, severity of neutropenia, treatment?

A

A disease of childhood caused by alpha‐neutrophil antibodies

•Average age of onset: 6‐12 months
•Moderate to severe neutropenia
•Spontaneous remission over 2 yrs: 95%
•Treatment: Prophylactic antibiotics; G‐CSF only with severe/recurrent infection

Hematology (20 decks)

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