Leukemias+Myeloproliferative Disorders

Polycythemia Vera (P Vera)

PP: overproduction of RBCs in bone marrow→excess RBCs→hyperviscosity→decreased cerebral blood flow/hypercoagulability

RF: 60+
middle-aged men
rare
2/1000 gen pop

E: m/c→thrombosis
peptic ulcer dx

CM: after bath→pruitis
headache
dizziness
tinnitus
blurred vision
erythromelagia
splenomegaly
facial plethora
engorged/enlarged retinal veins

DX: clinical
history

CBC
hemoglobin→increased
hematocrit→increased
-males→54%
-females→51%

erythropoietin level→low (primary p vera)

TX: 1st line→serial phlebotomy
-avoid excess iron supplements

P: indolent dx→15 yrs life expectancy
acute myelogenous leukemia→5%

Essential Thrombocytosis (Not A Condition)

PP: production of megakaryocytes in bone marrow→highly elevated platelet count

E: m/c→middle-aged women
rare

CM: at dx→asx
or
headache
erythromelalgia
thrombosis

DX:
CBC+diff
over 1-2+ million platelets→marked thrombcytosis
hemoglobin→normal
hematocrit→normal

TX: 1st line→hydroxyurea
no mx procedures→aspirin daily x long-term

P: indolent
myelofibrosis→10-15%
acute myelogenous leukemia→1-5%

Primary Myelofibrosis (MF)

PP: PDGF→ triggers excess fibrous tissue grows in bone marrow→bone marrow fills with scar tissue→extramedullary (outside of bone marrow) hematopoiesis+massive splenomegaly

E: platelet-derived growth factor (PDGF)
50+ y/o

CM: extramedullary (outside of bone marrow) hematopoiesis→fatigue+bleeding
massive splenomegaly→abdominal pain+early satiety
bone pain

DX:
peripheral smear→teardrop poikilocytosis

bone marrow biopsy
needed for dx
inaspirable (can’t get out liquid from bone)
fibrotic bone

TX:
mild→blood transfusion PRN
cure→allogenic stem cell transplant+matched sibling donor

P: poor
medial survival rate→5 years

Myelodysplastic Syndrome

PP: ineffective+dysplastic production of myeloid WBCs→cytopenias
abnormal cell mutation

E: 70 y/o
incidence increases with age
male
prior chemotherapy
prior radiation therapy
tobacco
benzene

CM: fatigue
infections
bleeding+bruising

DX: r/o pancytopenia ddx
-alcohol
-mx
-vitamin deficiencies
-infxns

+
CBC→persistent cytopenias

PS→dysplastic cells

BMBX→cytogenic/molecular features

TX:
low risk+asx→observation

cytopenias

• blood transfusions

• EPO

• romiplostim

• granulocyte colony stimulation factors

higher risk+worse cytopenias

• azacytidine

• lenadilodmide

• luspaterncept

• etc.

P: poor→2 year life expectancy
acute myelogenous leukemia

Acute Myelogenous Leukemia (AML)

PP: clonal production of abnormal+immature myeloid cells

RF: myeloid dysplastic syndrome (MDS)
myeloproliferative neoplasms (MPNs)
CML

E: 65-71 y/o (m/c→elderly)
idiopathic
previous radiation therapy
previous chemotherapy
benzenes

CM: fatigue
weakness
dyspnea
persistent gingival bleeding
chronic nosebleed
easy bruising
persistent mehorrhagia
persistent infxns→fever

PE: pallor
petechia
purpura
leukemia cutis

DX:
CBC
hallmark→pancytopenia+circulating blasts

PS
aurer rods

BMBX
confirmation
hypercellular→over 20%+ blasts

cell line
variable cytopenias in all 3 tests

cytogenics
confirmation

flow cyometry
confirmation

TX: look at tx process slide
60 y/o+under→chemo+allogenic stem cell transplant

over 60+ y/o:
lower dose chemo+lower intensity stem cell transplant
other chemotherapy

C: leukostasis
DIC
tumor lysis syndrome
CNS dx
AHA
severe infxns

P:
influenced by:
-clinical features
-cytogenic features
-molecular features

Allogenic Stem Cell Transplant Process

1. pt undergoes conditioning regimen
   -high dose chemotherapy→total body irradiation
   -kill remaining cancer cells+eradicate bone marrow→weakens pt’s immune system

2. pt receives donor stem cells

3. wait for stem cell growth+manage complications/side effects

complications

• mucositis

• nausea

• vomiting

• graft-versus-host dx (GVHD)

• serious infxn

• veno-occlusive dx

• graft failure

Acute Lymphoblastic/Lymphocytic Leukemia

A Little Leukemia

PP: clonal proliferation of abnormal+immature lymphoid cells

RF: down syndrome
hispanic

E:
peaks
-m/c→2-5 y/o (peds→60% of all cases)
-50 y/o

CM: sudden fevers
bone pains
fatigue→50% peds
pallor
infection
abrupt headache
vision changes

PE: lymphadenopathy
hepatosplenomegaly

DX:
CBC
WBC→5-100K
anemia
NTP
decreased platelets
blasts

confirmation→BMBX
hypercellularity→over 20%+ blasts

lumbar puncture
spinal fluid→blasts

immunophenotyping→flow cytometry

genetic+molecular profiling/classification→cytogenics
-B cell lymphocytes→85%
-T cell lymphocytes→15%
-natural killer (NK) cells→under 1%

neuro→brain imaging

CT scan

ECG

TX: look at tx guidelines slide
remission stage
daunarubicin
vincristine
prednisone
asparaginase

prophx
LP
ommaya resevoir

tx stage
depends:
-age
-RFs
-leukemia cell genetics

C: CNS dx
DIC
leukostasis
tumor lysis sx
AHA
severe infxns

Philadelphia Chromosome

discovered in 1959

positive in 95% of chronic myelogenous leukemia (CML) pts

positive in 25% of acute lymphocytic leukemia (ALL) pts
-m/c in adults

imatinib (tyrosine kinase inhibitor)→8 yr survival rate
-20%-87% survival rate increase

Chronic Myelogenous Leukemia (CML)

PP: overproduction of differentiated myeloid cells
3 different phases
immature blasts in peripheral circulation→unlikely

E: 66 y/o
Old
Male

CM: m/c→asx
fatigue
Intermittent low-grade fever
Abdominal pain
Early satiety
Weight loss
Excess sweat
Splenomegaly

DX:
1st line: PCR→bcr/abl gene

staging→BMBX

CBC
chronic
leukocytosis
bone marrow→under 5% blasts
universal→absolute basophilia
eosinophilia

accelerated
progressive decreasing of RBCs+platelets
bone marrow→5-20% blasts

blast phase
worsening cytopenia
bone marrow→over 20% blasts

TX:
chronic
tyrosine kinase inhibitor
-imatinib
-dasatinib
-nilotinib
-bosutinib
-asciminib
bcr/abl blood test q3 months

accelerated/blast
tyrosine kinase inhibitor+chemo
spleen transplant

Chronic Lymphocytic Leukemia (CLL)

PP: malignancy of mature+monoclonal B lymphocytes→myeloproliferative neoplasm
same dx as small lymphocytic leukemia (SLL)
-CLL→blood
-SLL→lymph nodes

E: 70 y/o (m/c→elderly)
male
m/c form of leukemia

CM: asx
or
recurrent infxns
hepatosplenomegaly (50%)
lymphadenopathy (80%)

stage 1→lymphocytosis+LAN
stage 2→organomegaly
stage 3→anemia
stage 4→thrombiocytopenia

DX: incidental dx
1st line: CBC+diff→isolated lymphocytosis (under 5k)

WBC
under 20k
mature lymphocytes 75-98% of WBC count

peripheral smear
small+mature lymphocytes+darkly stained nucleus
smudge cells

BMBX→small lymphocytes

TX:

• venetoclax

• obinutuzumab

• ibrutinib

• acalabrutinib

• zanubrutinib-bruton

• tyrosine kinase inhibitors

Hyperleukocytosis

PP: WBC count over 100,000
symptomatic dx→leukostasis

Diff DX:
acute myeloid leukemia (m/c)
acute lymphoblastic leukemia
chronic lymphoblastic leukemia
chronic myeloid leukemia

Peripheral Smear

counts numbers of cells

identifies abnormal cell shape/features

identifies any immature cells

• RBC

• WBC

• platelets

Bone Marrow Biopsy

blood cancer→necessary

aspiration of fluid+core biopsy of bone

gives info about cells+marrow architecture

• presence of cancer cells

• percent of cancer cells

• bone marrow cellularity

• bone marrow fibrosis

Flow Cytometry

uses antibody labeling

identifies

• WBC types (immunophenotyping)

• cluster of differentiation (CD)

-peripheral blood
-BM aspirates

• lymphoid or myeloid

• specific WBC type

• T cells vs B cells

• CD4 vs CD8

Immunohistochemistry

uses antibody stains+looking under microscope

identifies

• WBC types (immunophenotyping)

• cluster of differentiation (CD)

-peripheral blood
-BM aspirates

m/c→solid tumors (lymphoma)

Cytogenic Tests

performed on BMBX/peripheral blood cells

determines genetic+chromosomal abnormalities

3 basic test types

• karyotyping

• FISH
  -fluorescence in-situ hybridization

• CMA
  -chromosomal microarray analysis

Bone Marrow/Stem Cell Stem Cell Transplanty

I: BM cancer (leukemia)

performed in specialized centers

prophx: induction chemotherapy→clears BM of cancer cells→healthy stem cells infused back into BM

2 general types

• allogenic→matched donor

• autologous→from pt

Leukemia vs Lymphoma

leukemia→bone marrow

• can occur in both myeloid+lymphoid lineages

• remains liquid

lymphoma→lymphatic system

• occurs only in lymphocytes
  -lymph nodes
  -spleen
  -other lymph tissue

• forms solid tumors

Clonal Hematopoiesis

mutated stem cell→goes rogue+starts cloning itself

immature→acute

chronic→mature

Blasts

immature WBCs

low percentage→necessary in BM (under 10%)

acute leukemias→blasts can’t differentiate
-in peripheral blood (hallmark)

chronic leukemia→overproduction of mature blasts

ALL: Classification

flow cytometry→classified by cell type origin

b cell lymphocyte→85%

t cell lymphocyte→15%

natural killer (NK cells)→under 1%

ALL: CNS Prophylaxis

leukemic cells pass through BBB→high rate of penetration into CNS
-chemo+mx can’t cross

intra-thecal prophx tx→all pts

• ommaya resevoir

• lumbar puncture

l/c→brain/CNS radiation

ALL: Tx Guidelines

induction

1. goal: destroy BM→intense chemo

2. BM aspiration→check for any measurable residual dx (MRD)

consolidation

• goal: eliminate remaining leukemic cells

• chemo regimen
  -determined by amount of measurable residuable dx (MRD)

• chemo replacement (young adults/adults+high risk features)→hematopoietic stem cell transplant (HSCT)

maintenance

• goal→prevent relapse

• chemo weekly x 2-3 yrs
  -excellent initial response+lower risk pt→omit

ALL: Prognosis

overall→90% children cured
-may have long-term toxicities

worsening RFs

• T cell

• cytogenic features

• under 1 y/o

• over 10+ y/o

• CNS disease

• WBC→over 50k+

AML: Hyperleukocytosis+Leukostasis

hyperleukocytosis

• WBC count over 100k+

• in leukemia pt

• increased viscosity→lots of blasts that don’t bend well

leukostasis

• symptomatic hyperleukocytosis
  -visual changes
  -headache
  -dizziness
  -tinnitus
  -confusion
  -dyspnea

• m/c→AML

• other leukemias→uncommon

AML: Classification

divided by genetic abnormalities

over 10% blasts on BMBX→defining mutation

without defining mutation

special categories

• therapy-related

• acute promyelocytic→bad

• myeloid sarcoma

• other

AML: Tx Indications

fitness level+comorbidities
-eligible for induction chemo

molecular/genetic classification
-specific mutations→specific txs

prognostic categories
-favorable
-intermediate
-adverse

AML: Tx Process

induction

1. goal→reduce tumor burden→clear as many leukemic cells as possible→achieve complete remission

2. intense 7+3 chemo regiment
   -require hospitalization

3. BMBX→check measurable residual disease (MRD)

consolidation

• goal→eliminate any remaining leukemic cells
  -regimen→determined by MRD+RF profile

• CR+high risk→allogenic hematopoietic stem cell transplant

• no CR→more chemo

• CR+low risk→move on to maintenance

maintenance

• goal→prevent relapse

• more chemo/targeted mxs for a year

• followed by close surveillance

AML: Prognosis

varies based on

• fitness

• age

• mutations
  -TP53→bad
  -del(17p)→bad

60-80% younger adults→get CR
cure→only 30%

refractory+relapsed dx→bad

• refractory→2 courses of induction→no CR

• relapse→cancer returns after remission

CML: Stages

chronic phase

• indolent

• more mature cells

• asx

accelerated phase

• gradual loss of immature stem cells→differentiate→more blasts+sxs

blast crisis

• resembles acute leukemia

CML: Prognosis

imatinib→improved dramatically

tx not curative

resistance to tx+progression to accelerated and blast phases eventually occur

tx+outcome determination→prognostic scoring models

5 year relative survival→70.4%

CLL: Prognosis

typically indolent sx

tx not curative

eventually most will become tx-resistant with worsening cytopneias

medial survival→10-15 yrs

Myeloprolipherative Neoplasms (General)

PP: clonal hematopoeitic stem cell disorder
proliferation of one or more myeloid lineages→pancytosis of peripheral blood
-RBC
-platelets
-granulocytes

E:
types

• essential thrombocythemia (ET)
  -overproduction of platelets

• polycythemia vera (PV)
  -overproduction of RBCs

• CML
  -overproduction of granulocytes

• primary myelofibrosis (PMF)
  -overstimulation of marrow fibroblasts→BM fibrosis

CM: similar to CML
opposite of MDS

P: AML

Myeloprolipherative Neoplasm Mutations

MPN→result of 3 specific somatic driver mutations

• janus kinase 2 gene (JAK2)

• calreticulin gene (CALR)

• myeloproliferative leukemia gene (MPL)

• also common→familial clustering

Essential Thrombocytopenia

PP: too many platelets

E: type of myeloproliferative neoplasm
60 y/o
female
probability increases with age

CM: m/c→asx
or
vasomotor

• headache

• dizziness

• visual disturbances

• erythromelagia

• acral paresthesia

• livedo reticularis

abdominal pain→splenomegaly

DX:
platelet 450k+
+
confirmation
-JAK2
-CALR
-MPL
+
BMBX→megakaryocyte CML
+
r/o CML

TX:
based on risk assessment

high risk

• cytoreductive tx+low-dose aspirin

intermediate risk

• cytoreductive tx

• low-dose aspirin

low risk

• low-dose aspirin

very low risk

• observation

• low-dose aspirin

C: stroke
MI
blood clots
pregnancy loss

P: most pts→normal life expectancy
progression to AML
worse
-60+ y/o
-thrombosis hx
-JAK2 mutation