9 - Chronic Myeloid Leukemia and Myeloproliferative Neoplasms

Question 1

Myeloproliferative Neoplasms - Specific disorders

Answer 1

Chronic Myeloid Leukemia
Polycythemia Vera
Essential Thrombocytosis
Primary Myelofibrosis
Chronic Eosinophilic Leukemia
Systemic Mastocytosis

Question 2

Myeloproliferative Neoplasms

Answer 2

Excess of mature myeloid cells
Usually of single lineage
Often some overlap
Activating mutations in Tyrosine Kinases are common

Question 3

Chronic Myeloid Leukemia - Epi

Answer 3

Presents 45 - 55, but incidence increases with age. 12 - 30% are >60
M>F (1.3:1)
50% diagnosed by routine labs
85% diagnosed during chronic phase

Question 4

Chronic Myeloid Leukemia - Symptoms

Answer 4

Fatigue
Abdominal fullness
Fever, Chills, Sweats, Weight Loss

Question 5

Chronic Myeloid Leukemia - Physical Findings

Answer 5

Hepatosplenomegaly

Ecchymoses

Question 6

Chronic Myeloid Leukemia - Common Labs

Answer 6

Increased mature and immature myeloid cells
Basophilia
Anemia
Thrombocytosis

Question 7

Chronic Myeloid Leukemia - Peripheral Blood Smear

Answer 7

Immature cells in the myeloid lineage

More committed than the blast cells, but still immature

Question 8

Chronic Myeloid Leukemia - Bone Marrow

Answer 8

Hypercellular with increased Myeloid-to-Erythroid ratio

Question 9

Chronic Myeloid Leukemia - Genetics

Answer 9

The Philadelphia Chromosome
t(9;22)
BCR-ABL gene fusions

Quantitative Reverse Transcriptase PCR detecting BCR-ABL can evaluate disease burden

Question 10

Chronic Myeloid Leukemia Response to Therapy - Hematologic Response

Answer 10

Complete:
Normal peripheral blood count
WBC

Question 11

Chronic Myeloid Leukemia Response to Therapy - Cytogenetic Response

Answer 11

Major:
Complete: 0% Ph+ cells
Partial: 1% - 35% Ph+ cells

Minor: 36% - 95% Ph+ cells

Question 12

Chronic Myeloid Leukemia Response to Therapy - Molecular Response

Answer 12

MR3 (“Major”): >3 log reduction in BCR-ABL transcripts from baseline
MR4.5 (“Complete”): >4.5 log reduction

Question 13

CML Survival

Answer 13

4ish years median surivval

Question 14

CML Phases

Answer 14

Chronic (Median 4 -6 years)
Accelerated (Variable duration)
Blast Crisis (Median survival 3 - 6 months)

Question 15

CML - If a patient responds to Interferon treatment

Answer 15

The prognosis from then on is usually good!

Question 16

CML - If a patient doesn’t respond to Interferon treatment

Answer 16

The prognosis is as if they had no treatment at all

Question 17

The only way to cure CML

Answer 17

Allogeneic Stem Cell Transplant

Question 18

Imatinib - Mechanism of action

Answer 18

Binds to the ATP binding site of ABL, preventing the transfer of phosphate groups to other proteins, blocking downstream signaling!

Question 19

Imatinib - Side Effects

Answer 19

Bone marrow suppression:
Leukopenia
Anemia
Thrombocytopenia

GI:
Nausea
Vomiting
Diarrhea

Question 20

Imatinib - Metabolism

Answer 20

Well absorbed PO
Hepatic metabolism
Cytochrome P450
Majority excreted in biliary tract as metabolites with only a small percent unchanged
Doses must be adjusted in patients with severe liver disease.

Question 21

CML - Patients who attain MR3 with Imatinib treatment

Answer 21

Have better survival

Question 22

What can cause imatinib resistance?

Answer 22

DDIs
Adherence issues
Multiple copies of the Ph chromosome
Mutations in ABL

Question 23

Clinical indications of Imatinib and other TK inhibitors

Answer 23

Ph+ diseases (ABL)
CML
Ph+ ALL
C-kit diseases
GIST

Question 24

Polycythemia Vera

Answer 24

Elevated Hgb/Hct on lab testing

Thrombosis

Question 25

Polycythemia Vera - Symptoms

Answer 25

Pruritus - especially after showering Plethora (Ruddy complexion) Abdominal fullness/early satiety (splenomegaly)

Question 26

Polycythemia Vera - Most common mutation

Answer 26

JAK2 in the Pseudokinase domain | Results in downstream anti-apoptotic signaling through JAK2 in the absence of Erythropoietin

Question 27

Polycythemia Vera - Bone Marrow

Answer 27

``` Moderate to marked hypercellularity Increased hematopoiesis Maturation intact Large clustered megakaryocytes Decreased/absent iron stores Increased reticulin fibers in a minority of cases ```

Question 28

Polycythemia Vera - Diagnostic criteria

Answer 28

Major: Hgb > 18.5 in men or > 16.5 in women or other evidence of increased RBC volume Presence of JAK2V617F or JAK2 exon 12 mutation Minor: Hypercellular bone marrow with trilineage hematopoiesis Low serum erythropoietin Endogenous enrythroid colony formation in vitro Diagnosis requires both major criteria of elevated Hgb & 2 minor criteria

Question 29

Polycythemia Vera - Differential

Answer 29

``` Chronic Hypoxia (Altitude, cigarettes, sleep apnea, pulmonary disease) Erythropoietin abuse Familial erythrocytosis (mutation in Epo R) ```

Question 30

Polycythemia Vera - Clinical Course

Answer 30

Overall mortality 3% per year Thrombosis (increased by age >65 and prior thrombosis) Bleeding Transformation to AML (influenced by duration of disease) Myelofibrosis ("spent phase") - More common in age>70

Question 31

Polycythemia Vera - Management

Answer 31

Therapeutic phlebotomy (Maintain Hct

Question 32

Polycythemia Vera - Management - Cytoreduction

Answer 32

Consider cytoreduction if: Patient is intolerant of phlebotomy Thrombosis develops Symptomatic or progressive splenomegaly age 40: Hydroxyurea (Hydroxycarbamide)

Question 33

Essential Thrombocythemia (Essential Thrombocytosis) - Clinical presentation

Answer 33

Elevated PLT on labs Thrombosis Symptoms: Pruritus - Especially after showering Erythromelagia (Severe pain in hands/feet) Abdominal fullness/early satiety (splenomegaly)

Question 34

Essential Thrombocythemia - Genetics

Answer 34

50% of cases - JAK2 mutation, similar to Polycythemia vera Why the same mutation leads to two diseases is unclear, but may have to do with allele burden. 5% have point mutations in mpl

Question 35

Essential Thrombocythemia - Diagnosis

Answer 35

Sustained platelet count > 450,000/μL for at least 2 months Bone marrow showing primarily megakaryocytic proliferation No evidence of WHO diagnosis of Polycythemia Vera, Primary myelofibrosis, CML (BCR-ABL translocation), MDS or other myeloid neoplasms JAK2V617F mutation or other clonal marker (mpl mutation) or in the absence of a clonal marker, no evidence of reactive thrombocytosis

Question 36

Essential Thrombocythemia - Differential Diagnosis

Answer 36

``` Reactive elevation of platelet count: Iron deficiency Inflammation/Infection Surgery Splenectomy Connective tissue disease Metastatic cancer Lymphoproliferative disease ``` Polycythemia Vera Chronic Myeloid Leukemia

Question 37

Essential Thrombocythemia - Clinical Course

Answer 37

Uncertain if ET compromises life span Thrombosis (higher in patients > 60 w/previous history of thrombosis, cardiovascular risk factors, JAK2V617F mutation) Bleeding - Higher in patients with plt>1,500,000 Myelofibrosis (4 - 8% at 10 years) AML (1% in untreated patients)

Question 38

Essential Thrombocythemia - Management

Answer 38

All: Aggressive management of cardiovascular risk factors Low risk: (Age 60, prior thrombosis, cardiovascular risk factors) Low dose aspirin + hydroxyurea Consider anagrelide or interferon alfa if hydroxyurea intolerant

Question 39

Primary Myelofibrosis - Clinical Presentation

Answer 39

Abdominal fullness (due to splenomegaly) Splenomegaly (due to extramedullary hematopoiesis) Symptoms of anemia (Fatigue, pallor, dyspnea on exertion) Bleeding/bruising Infection Cachexia

Question 40

Primary Myelofibrosis - Bone marrow

Answer 40

Hypercellular Megakaryocytic hyperplasia Pleomorphism of megakaryocytes Granulocytic/erythroid maturation intact Fibrotic phase - Loss of hematopoiesis (megakaryocytes spared) Osteosclerosis - Increased osteoclasts and osteoblasts

Question 41

Primary Myelofibrosis - Peripheral blood smear

Answer 41

``` Teardrop RBCs Leukoerythroblastic features (peripheral blood looks like marrow) ```

Question 42

Primary Myelofibrosis - Major Diagnostic Criteria

Answer 42

Major: Hypercellular marrow with megakaryocytic atypia and reticulin and/or collagen fibrosis WHO diagnostic criteria for Polycythemia Vera, CML, ET, MDS or other myeloid neoplasms excluded Presence of JAK2V617 or other clonal marker OR in the absence of a clonal marker, no evidence of reactive fibrosis ``` Minor: Leukoerythroblastosis Elevated LDH Anemia Splenomegaly ``` Diagnosis requires all major criteria AND 2 minor criteria

Question 43

Primary Myelofibrosis - Clinical Course

Answer 43

Variable life expectancy - Average 5 years Months to decades ``` Risk factors: Age > 65 yo Hgb 25k/μL Blasts > 1% Constitutional symptoms RBC transfusion dependence Unfavorable karyotype (eg +8, abnl 7 or 5, 12p-, inv3, 11q23 rearrangement) Plt ```

Question 44

Calreticulin

Answer 44

Target of autoantibodies in SLE and Sjogrens Major calcium storage protein in the ER Inhibits binding to Glucocorticoid Response Element in the nucleus Regulates gene transcription

Question 45

Primary Myelofibrosis - Calreticulin mutation

Answer 45

Better survival than with JAK2 mutation or mpl

Question 46

Primary Myelofibrosis - Management

Answer 46

Supportive measures: Erythropoietin/transfusions Hyrdroxyurea Splenectomy/splenic radiation Active Therapy: Stem cell transplant Thalidomide/corticosteroids Jak inhibitors

Question 47

Primary Myelofibrosis - Ruxolitinib

Answer 47

Reduces splenomegaly and improves survival