Myeloproliferative disorders and leukemia Flashcards
1
Q
Stem cells
A
- Can self-renew (by dividing into 2 stem cells or 1 stem cell and 1 progenitor)
- Can differentiate into more mature cells (by dividing into 1 stem cell and 1 progenitor, or dividing into 2 progenitors)
2
Q
Myeloproliferative disorders
A
- Are acquired clonal hematopoietic SC disorders (the source is a single mutated cell- the rest are clones of it)
- Can be variable effects on differentiation of the myeloid progenitors
3
Q
Ways to identify clonality
A
- Look at genetic or molecular changes (will be found in all clonal cells)
- XCIP: random inactivation of X chrom in females by looking at X-linked proteins (G6PD) to see if its far from 50/50
- Surface Ag expression: K:L expression on B cells should be 2:1 ratio
4
Q
Chronic myeloid leukemia (CML)
A
- Most common myeloproliferative disease
- Associated w/ Philadelphia chromosome t(9,22), the first model of molecular targeting for cancer Rx
- The t(9;22) translocation moves the BCR gene (22) to the ABL gene (9) creating a Bcr-Abl fusion (chimeric) protein
- The Abl normally is a tyrosine kinase, but the fusion protein renders the kinase constitutively active
- This causes increased signaling and proliferation
5
Q
Ways to Dx CML
A
-FISH will show if there are translocations, so if you test for chrom 9 and 22 and the two fluorescent dots are right next to each other
6
Q
Phases of CML
A
- In the chronic phase of CML the pt has a normal Hb and plt count but a high WBC (these WBCs are mature granulocytes, mostly PMNs but w/ high than normal neutrophils)
- At some point the chronic phase will turn in an acute, blast phase
- The blast phase occurs when additional mutations accumulate in precursor cells and lead to blasts that are unable to further differentiate
- The blast phase can be either acute myeloid leukemia (AML) or acute lymphoid leukemia (ALL)
7
Q
Differences btwn chronic and blast phase CML
A
- Chronic phase: myeloproliferative disease, mainly in granulocytes, last yeast, present w/ splenomegaly, leukocytosis, Hb and plts usually normal
- Blast phase: transform into acute myeloid (70%) or acute lymphoid (30%) leukemia, fatal in weeks-months if not treated, poor response to standard AML/ALL Rx, present w/ anemia and thrombocytopenia
8
Q
CML Rx
A
- Allogenic HSC Tx the only cure
- Non-specific cytotoxic CRx: hydroxyurea, cytarabine
- Targetted Rx: block the signal of the tyrosine kinase chimeric protein (bcr-abl) by imantinib (gleevec)
9
Q
Polycythemia vera (PV)
A
- Acquired clonal hematopoietic stem cell disorder characterized by elevated RBC mass/Hb
- Is a myeloproliferative neoplasm (MPN)
- Variable degree of leukocytosis and thrombocytosis
- EPO is suppressed
- Present w/ splenomegaly
- Venous and arterial thrombosis is major morbidity
- Often report: “itching after bathing”
10
Q
PV molecular mechanism
A
- Abnormal constitutive activation of JAK2
- JAK is a normal signal tyr kinase that is activated upon the binding of EPO or TPO
- In PV the constitutive activation of JAK leads to upregulation of its activity in myeloid precursors
- The signal from JAK induces growth of the cell, thus increasing the Hb
- In response the kidneys stop producing and releasing EPO
- But JAK2 isn’t the only cause of the disease, and an earlier mutation (TET2) may increase the chance of developing a JAK2 mutation
11
Q
Causes of erythrocytosis
A
- Primary causes: PV, congenital EPO receptor anomalies
- Secondary causes: mutations resulting in increased EPO (VHL, HIF2a, PHD), 2,3 DPG deficiency, high-affinity Hb, hypoxia, renal EPO-overproduction, EPO-producing tumors
12
Q
PV Dx criteria
A
- 1 major + 2 minor or 2 major + 1 minor
- Major: high Hb, JAK2 mutation
- Minor: BM trilineage hyperplasia, suppressed EPO, spontaneous endogenous erythroid colonies (EEC)
13
Q
PV clinical course
A
- Asymptomatic from mo-yrs w/ increase RBC mass (Hb/Hct)
- Then develop hyper viscosity symptoms (controlled w/ periodic phlebotomy)
- Then leukocytosis/thrombocytosis: at risk of thrombosis and may need cytoreductive Rx
- Progression to myelofibrosis after 15-20 yrs (develop anemia, progressive splenomegaly)
- Progression to acute leukemia after 20 yrs
14
Q
Essential thrombocytosis (ET)
A
- Chronic condition characterized by elevated plt counts (MPN)
- Must rule out secondary causes: infectious + inflammatory disorders, malignancy (all from increased IL6-> increased TPO, or from increase in megs), Fe deficiency
- 50% harbor JAK2 or cMPL mutation
- Major complication: arterial and venous thrombosis
- Lower rate of transformation to myelofibrosis and/or acute leukemia (10%)
- Can see fluffy megs in clusters in the BM
15
Q
Myelofibrosis (MF)
A
- Can be primary or a late complication of PV/ET
- Is a MPN
- 30-50% harbor JAK2 mutations
- Patients usually have progressive splenomegaly (“biggest spleen you will ever palpate”)
- Anemia often progressive, transfusion-dependence common
- Shortened life span (unlike ET/PV)
- Allogenic HSC Tx only cure but high morbidity and mortality
16
Q
Pathology of MF in PBS and BM
A
- PBS: Can see early myeloid cells, and nucleated RBCs
- PBS: Most distinctive is the tear-drop RBCs
- BM: can stain w/ reticulin to look at the fibrosis, will appear black
17
Q
Leukemogenesis
A
- 2 things lead to acute leukemogenesis: differentiation block and enhanced proliferation
- Differentiation block due to LOF of transcription factors needed for differentiation
- Enhanced proliferation due to GOF mutations of tyr kinases
18
Q
Acute vs chronic leukemias
A
- Acute: rapid onset (days-weeks), due to malignant clonal event and a block of differentiation
- Have an increase in immature (blast) cells that do not differentiate or mature
- Chronic leukemia: chronic onset (months-years), due to malignant clonal event w/o block of differentiation
- Leads to increase number of mature cells that do not die or undergo apoptosis
- Both acute and chronic can manifest as lymphoproliferative or myeloproliferative forms
19
Q
ALL vs AML in PBS
A
- In an ALL PBS you see many lymphoblasts
- The WBCs will have a much higher N:C (nuclear to cytoplasm ratio), w/ the nucleus making up almost the entire cell
- Need CNS prophylaxis in ALL
- In AML PBS you see many myeloblasts
- The WBCs will have a lower N:C and they will have granules and auer rods in the cytoplasm
- Auer rods ONLY in AML, never ALL (will be tested)
20
Q
Causes of acute leukemias
A
- Idiopathic (most)
- Underlying hematologic disorders and hereditary conditions
- Chemicals, drugs, radiation
- Viruses (like HTLV1-> TCLL)
21
Q
Adult vs children acute leukemias
A
- Adult acute leukemias are usually fatal w/in weeks to months w/o chemo
- CRx in adults leads to high mortality from Rx-related complications (unlike in kids)
- ALL: mainly children (M>F), curable 70% in kids, rarely curable in adults
- AML: mainly adults (M>F), curable in minority of adults
- Rough age cut offs (estimates):
- 0-14: ALL
- 14-39: AML
- 40-60: CML
- > 60: CLL
22
Q
Presentation of acute leukemias
A
- BM failure: anemia, thrombocytopenia, neutropenia/leukopenia
- Organ infiltration: enlargement of liver, spleen, LNs, gum hypertrophy, bone pain, other organs (CNS, skin, testis)
- Constitutional symptoms: fever, sweats, weight loss
23
Q
Dx of acute leukemias
A
- Defined by the presence of >20% blasts in BM
- Immunophenotyping to confirm (flow cytometry): myeloid lineage displays CD13 and CD33, lymphoid lineage displays CD5, CD7, and CD19
- Also use molecular genetics and cytogenetics (to identify mutations/chromosomal abnormalities)
- To determine if its AML vs ALL can look at nzs w/in the cell
- AML cells usually contain MPO (myeloperoxidase), which crystalizes into auer rods
- ALL cells usually contain TdT (DNA polymerase present in both T and B lymphoblasts), TdT is not present in mature lymphocytes (indicates blasts)
24
Q
AML features
A
- 5,000 from myelodysplasia (ineffective production) and 7,000 de novo (can only cure 25%)
- Prognostic features: status/comorbidities, antecedent hematologic disorder (MDS), age (over 65 almost always incurable), prior CRx (etoposide, anthracyclines lead to quick onset, alkylators and other CRx lead to MDS and take longer)
- Leukemic prognostic marker: leukocytosis extent (the higher the worse), cytogenetics, molecular markers (FLT3 is bad, NPM1 is good)
25
Q
APL: acute promyelocytic leukemia
A
- Specific form of AML that is due to t(15;17) leading to fusion of genes PML (15) to RAR (17), this creates a fusion (chimeric) protein PML-RAR
- The fusion protein leads to maturation arrest in myeloblasts
- Giving pharmacologic doses of ATRA removes the maturation arrest
- Typical findings: lots of purple granules, auer rods in blast cells in PBS, low fibrinogen/abnormal coag test, often DIC initiated due to contents of granules being full of TF
- Findings on FC: CD13, CD33
- If patient has DIC and thrombocytopenia (especially w/ the abnormalities on PBS) give them ATRA (analog of vit A) to overcome the maturation arrest and stop the DIC (there is no harm in giving ATRA)
- After ATRA give Arsenic trioxide
- Most curative AML (90% cure rate)
26
Q
Acute lymphoblastic leukemia (ALL)
A
- Typically in children, adults have poor prognosis especially if Ph+ (philadelphia chrom), which is 30% of pts
- Poor prognosis if it’s a T cell ALL (which is a lymphoma: presents in mediastinum as mass, usually in teenage boy)
- T cell ALL has best prognosis in adults (still not good)
- Require lots of CRx (including CSF and scrotal prophylaxis, and extended maintenance
- B lymphoblasts display CD markers CD10,19,20 under FLC
- T lymphoblasts display CD2-8 (do NOT display CD10)
27
Q
Prognosis of ALL
A
- Poor prognosis ALL: pre-T, pro-B, >35 yo, WBC (>30g/L in BCALL, >100g/L in TCALL), no remission after 4 wks of induction Rx
- Very poor prognosis: Ph+ philadelphia chromosome (same translocation from CML t(9;22)) and bcr-abl positive
- t(9;22) ALL translocation mostly in adults
- Better prognosis: t(12;21), which is mostly in kids (TEL), CALLA AL (pre-B, CD10+) also good prognosis in kids
- T cell ALL has best prognosis in adults (still not good)
28
Q
Rx of acute leukemias
A
- Rx influenced by type (ALL vs AML), age, and curative vs palliative intent
- Combination CRx: first goal is complete remission, further Rx to prevent relapse
- Supporitve medical care: transfusions, antibios, mutrition
- Psychosocial support: patient and family
29
Q
Phases of Rx in AML and ALL
A
- ALL: first induction, then intensification, then CNS prophylaxis, then maintenance
- AML: induction, then consolidation (post-remission Rx)
- One option is HSC Tx
- Complications in managing acute leukemias: leukostasis, DIC (mostly in APL), sepsis, tumor lysis
30
Q
Acute myeloid leukemia
A
- Clonal expansion of myeloid precursor cells w/ reduced capacity to differentiate, due to: block in differentiation, enhanced proliferation/self-renewal, resistance to apoptosis
- Pathogenesis: chromosomal translocation leading to altered transcriptional regulation, activate tyrosine kinase mutations (proto- oncogene) and tandem duplication, LOF mutations of TFs or tumor suppressors (p53), epigenetic alterations
31
Q
Clinical findings/symptoms of AML
A
- These are due to excessive proliferation of myeloid precursor cells in BM
- Functional neutropenia: infection, fever, chills
- Thrombocytopenia: bleeding/bruising
- Anemia: weakness and fatigue
- Bone pain (sternum and lower extremities): infrequent but thought to be secondary to expansion of medullary cavity
- Gingival involvement, retinal hemorrhage, pallor, petechiae, ecchymoses
- Bone tenderness, CNS infiltration, skin and soft tissue infiltration
- Rare hepatosplenomegaly or LAD (can occur in extra medullary disease)
32
Q
Dx of AML and classification
A
- Anyone w/ >20% myeloblasts in BM
- Also some cytogenic abnormalities classify pts as having AML regardless of blast percentage
- Classify based on morphology and histochemistry (MPO)
- Based on immunophenotyping (surface markers)
- Based on acquired chromosomal abnormalities (karyotyping, FISH)
- Mutations w/o chromosomal abnormalities (sequencing)
- Most important one for us: APL
33
Q
Goals for Rx of AML
A
- Complete remission from induction (does not mean that pt is cured, just disease is occult)
- Cure refers to the complete absence of neoplastic cells, which is only achieved after consolidation (5% blasts is normal)
- No maintenance for AML
- High risk pts get HSC Tx
- Want plt >100K, PMN >1000, BM ≤5% blasts
- Complete remission: detected by sensitive tests (PCR, FC) by revealing no evidence of neoplastic cells in BM
- Complete remission for >3 yrs w/o relapse means they are potentially cured (still 10% chance of relapse)
34
Q
Typical induction regimen: 7+3
A
- Combination CRx of 7 days of continuous cytarabine infusion + anthracycline days 1, 2, and 3
- For all new Dx AML except APL
35
Q
Consolidation Rx for AML
A
- Post first remission, if pt is <60 use 2-3 courses of high dose cytarabine (HSC Tx in high risk pts)
- If pt is ≥60 there is no standard approach (since both cytarabine and HSC Tx will be toxic), just supportive care
- AML prognosis in young adults: 70-80% achieve remission, 35-40% are alive after 5 years of remission
- AML prognosis in older adults: 45-55% achieve remission, 10-20% are alive 5 years after remission
36
Q
Prognostic factors
A
- Cytogenetics (classification of AML)
- Antecedent hematologic disorder (MDS)
- Age
- Favorable type: APL
- Unfavorable type: Ph+
37
Q
AML FLT3 mutation
A
- Most common mutation in AML (30%), mostly in pts w/ normal chromosomes
- Leads to activation of FLT3, a negative prognostic factor
- Inhibition of FLT3 a potential target for Rx
- FLT3 mutation results in constitutively active FLT3 (transmembrane tyr kinase) and thus increased proliferation
- NPM1 is a good prognostic factor
38
Q
Leukostasis
A
- Mostly in those w/ WBC >100K, but can also be seen in pts w/ WBC >50K
- Due to blast cells being less deformable that mature cells
- High metabolic activity of blasts and local production of cytokines contribute to hypoxia
- Symptoms of leukostasis: dyspnea, chest pain, headaches, altered mentation, CN palsies, occular symptoms, priapism (constitutively erect), MI
39
Q
Leukostasis Rx
A
- CRx w/ induction agents (cytarabine, anthracycline) or w/ high dose hydroxyurea
- Consider low dose cranial irradiation to prevent cell proliferation in CNS
- Avoid transfusion
- Leukapheresis is an option, but only temporary measure (does not affect established vascular plugs, limited benefit in underlying pulmonary symptoms following CRx, should be used adjunctively w/ CRx)
40
Q
Tumor lysis syndrome (TLS)
A
- Metabolic derangements caused by massive release of cellular components following lysis of malignant cells
- Commonly seen in malignancies w/ high rates of cell proliferation (ALL, Burkitt’s) but can also be seen in AML
- Presents w/ hyperphosphatemia, hyperkalemia, hyperuricemia, hypocalcemia, uremia
- Electrolyte abnormalities can occur w/o the entire spectrum of TLS or even before Rx is initiated
- Uremia implies renal failure (due to crystallization of uric acid and CaPO4 in renal tubes)
41
Q
TLS Rx
A
- Prevention and management: IV hydration, allopurinol (decreased formation of uric acid), recombinant urate oxidase (converts the uric acid to allantoin- highly soluble), dialysis
- Allopurinol a preventative measure, urate oxidase is rescuing measure
42
Q
DIC
A
- Seen in APL due granules containing TF and coag factors
- Widespread initiation in coag leads to fibrin deposition, microthrombi, and organ damage
- Depletion of fibrinogen and excessive production of plasmin leads to breakdown of fibrin (FPDs, D-Dimers) and bleeding
- High D-dimer test/FDPs, low fibrinogen, elevated aPTT and PT, thrombocytopenia, hemolytic anemia (schistocytes)
43
Q
DIC Rx
A
- Supportive Rx: plts, cryoprecipitate, FFP (fresh frozen plasma)
- Rx for obvious thrombosis (APC)
- Rx of underlying malignancy: ATRA
- For remission of APL use ATRA + Arsenic trioxide
- Side effects of ATRA: headache, bone pain, hypertriglyceridemia, dried mucous membranes/skin
- Retinoic acid syndrome: fever, respiratory distress, hypotension, plueral/pericardial effusions, lower extremity (LE) edema, renal failure
- Thought to be due to cytokine release and/or release of promyelocytes from BM after ATRA Rx
- Higher WBC leads to higher risk, use CRx at same to reduce risk
44
Q
CNS involvement
A
- Occurs in less than 5% of AML patients
- Only do LP if symptoms suggest CNS involvement
- Findings in CSF: blast cells, increase in protein, decrease in glc
- Rx: intrathecal CRx and possibly whole brain XR Rx
- Highest incidence of CNS involvement: relapsed APL
- Common to administer CNS prophylaxis in relapsed APL
45
Q
Ocular involvement
A
- In over 60% of newly Dx AML pts
- Commonly choroid and retina (hemorrhage and cottage cheese exudate)
- Can involve conjunctiva and lacrimal glands
- Rx w/ common induction CRx and possible plts Tx
46
Q
Other complications
A
- Necrotizing enterocolitits (usually post CRx)
- Joint involvement in setting of leukemic blast synovial membrane infiltration
47
Q
Rx for refractory or relapsed AML
A
- Duration of first remission most important predictive factor for outcome in relapsed/refractory AML
- Relapse is defined by >5% blasts in BM
- If remission is >1yr then relapsed prognosis is 40-60%, if remission is shorter then prognosis is 10-15%
- HSC Tx is option
