Lecture 47 - Clinical Aspects of Leukemia

Question 1

Myeloid vs Lymhpoid

Answer 1

Myeloid - Megkaryocytes, Eryhtrocytes, Basophils, Neutrophils, Eosinophils

Lymphoid: B and T Lymphocytes

Question 2

Acute vs Chronic

Answer 2

Acute — DNA damage leads to a maturation arrest;
Marrow is full of cells, but cytokines may be produced that lead to suppression of hematopeosis
Findings – Elevated immature WBCs + Hematopeoietic failure (anemia, thrombocytopenia, neutropenia)
patients become acutely ill
Medical Emergency

Chronic – No maturation arrest;
Elevated mature granulocytes;
Not acutely ill; not a medical emergency
Usually found incidentally in older patients

Question 3

6 Acute Leukemia Emergencies

Answer 3

Hyperluekocytosis: WBC thrombi 
Infection 
Bleeding (thrombocytopenia) 
DIC
Hyperuricemia --  Can lead to renal failure/electrlyte disturbance 

Tumor Lysis

Question 4

Treatment of:
Hyperleukocytosis
Infection

Answer 4

Hyperleukocytosis : Leukophoresis (mechanically draw out the WBCs), Hydroxyurea (cytostatic)

INfection: ABx

Question 5

Treamtment of:
DIC,
BLeeding

Answer 5

Bleeding – Platelets

DIC – Cryopreceipiate (replace fibrinogen + coags); platelets

Question 6

Treatment of Hyperuricemia, Tumor Lysis

Answer 6

Hyperuricemia: □ Treatment: Allopurinol (prevent uric acid formation), rasburicase (break down uric acid)

Tumor Lysis – hemodialysis, electrolytes

Question 7

Leukemia Treatment Outcomes:

Answer 7

Complete remission – normal blood counts, normal morphology

Cytogenic Remission – Normal Blood counts, morphologiy and cytogenetics

Molecular remission – normal Blood counts, morphologiy and cytogenetics + negative molecular findings

Question 8

Hematopeoitic Stem Cell Transplant

• how is it done?
• what are the different types of donors?
• what is the two fold effect?

Answer 8

What is it: Eradicating (myeloablation) the patient’s bone marrow and replacing it with healthy donor

Donors:
Donors should be Allogeneic – usually HLA identical relatives, but can be unrelated donors

Autologous Transplant – usually for Lymphoma

Syngeneic – Identical twin donates; But this has higher relapse rate as don’t have Graft vs Leukemia response

Two fold effect;

1) Eradicating unhealthy; and replacing with non diseased marrow
2) Graft Vs Luekemia — the new healthy cells will perceive the old as foreign and mount an immune response

Question 9

Acute Myeloid Leukemia:

• what is it?
• who gets it?

Answer 9

Accumulation of immature myeloid cells in the bone marrow and blood
Failure of normal hematopoiesis

Represents 80% of adult acute leukemia;

Question 10

• what are some causes of AML?

what are the effects on outcome

Answer 10

Causes: Biologically, Cytogenetically and Molecularly Diverse
1) t(8;21) — good outcomes; can be curative with chemo

2) Complex karotype – poorer prognosis

3) FLT3 Internal Tandem Duplication -
FLT3 – Growth Factor Receptor expressed on immature blasts in most AML cases
1/3 have Internal Tandem Duplication
Constituitive signaling of the Growth Factor Receptor
Therefore they respond to chemo, but it grows right back
High relapse rate

Question 11

Treatment of AMLs

Answer 11

Goal: Induce Remission
Chemotherapy +/- targeted Therapy

			□ Once in Remission -- further treatment to prevent relapse to reduce the burden of luekemia cells and eradicte residual disease  More Chemo -- (consolidate, intensify vs transplant)

Question 12

what is Acute Promyelocytic Leukemia?

• cause
• unique morphology
• Presentation
• treamtnet

Answer 12

(M3 Subtype of AML)
t(15;17) = PML/RAR
Large, Bi-lobed nuclei, Granules, Auer Rods
Present with DIC
Treatment: All-trans-retinoic Acid + Arsenic Trioxide

Question 13

• Chronic Myelogenous Leukemia
- what is it?

• cuase
  Treamtnet
  demonstration of Outcomes

Answer 13

High WBC, but lots of mature cells; may accelerate and transform to AML, ALL

cause: Biologically and Cytogenically Uniform –
Philadeplphia Chromosome: t(9;22) — BCR-ABL gene = fusion protien with tyrosine kinase activity

Treatment: Gleevec (Imatinib Mesylate) — BCRABL Inhibitor

Outcomes: need to demonstrate cytogenic and molecular remission

Question 14

• Acute Lymphoblastic Leukemia

• what is it?
• who gets it ?
• Treamtnet?

Answer 14

Immature lymphoid cells – either B or T
Peripheral blood with lots of lymphoblasts

Represents 80% of acute leukemia in children

Treatment: Induce Remission (chemotherpay +/- imatinib as up to 1/3 of ALLs can be BCR/ABLs)
○ Delay and Prevent relapse

Maintenance Chemotherapy — ALL only
§ 6 mercaptopurine

Question 15

Chronic Lymphocytic Leukemia

• what is it?
• who gets it?
• Treatments

Answer 15

• What: neoplasm Mature Lymphocytes; very indolent; slow progression
  
  • Who: Older Patients
  • Treatments:
  ○ FCR – Combination chemotherapy + antibody
  ○ BR –
  ○ Newer:
  § Ibrutinib – bruton’s tyrosine kinase
  § Idelalisib
  ○ Transplant

Question 16

• Non Leukemias: Myelodysplastic Syndromes

• what is it?
• risk stratification and associated treatments

Answer 16

What is it: Clonal Bone marrow disorder- – Ineffective hematopoiesis —
abnormal morphology of all lineages; cytopenias

Risk based on: Number of cytopenias, blast %, cytogenetics

Low risk: 
 If primarily Anemia -- 5q deletion 
		Use lenalidomide 
f Low Erythropoeisis ---
		Use EPO 
If Neutropenia/thrombocytopenia -- -
               Demethylating agents 

Higher risk: Poorer Prognosis
- Thnk Transplant in good candidate
Demethylating agents

Question 17

How do demethylating agents treat myelodysplastic syndromes?

Answer 17

§ Demethylation Cytosine Analogs – -inhbition of Methylation
□ Theory — too much methylation is causing maturation arrest
□ Inhibition of maturation lead to normal blood counts

Question 18

• Non Leukemias: 	Myeloproliferative Disorders 
- 
what are the different types?
what are there characteristic findings? 
Treatment for each

Answer 18

Polycytehemia Vera – Too many red cells;
Treatment: Get blood count under control:
(Phlebotomy, hydroxyurea, interferone, Jak2 Inhibitor)

Essential Thrombocythemia – too many platelets
Treatment: Get blood count under control
(hydroxyurea, intereferon)

Myelofibrosis – scarring of the bone marrow (most severe)
Treamtnet: Jak2 Inhibitors

Question 19

What is the name of the Jak2 Inhibitor?

Answer 19

Ruxolitinib