Lecture 10.1: Myelodysplasias and Myeloproliferative Syndromes

Question 1

Myelodysplastic syndromes are associated with what enviornmental exposures?

Answer 1

Radiation and benzene

Question 2

What are the most common offenders associated with therapy-realted Myelodysplastic syndromes?

Answer 2

• Alkylating agents: cyclophosphamide, ifosfamide, cisplatin, busulfan, nitrosourea, or procarbazine
• Anthracycline antibiotics: adriamycin, daunorubicin, epirubicin

Question 3

Some myelodysplastic syndromes in adults have which recognizable germline mutation?

Answer 3

germline GATA2, RUNX1 or telomere repair gene mutations

Question 4

Myelodysplastic syndromes are disorders of which cells and are characterized by what?

Answer 4

• Disorders of the pluripotent stem cell
• Characterized by ineffective hematopoiesis –> pancytopenia w/ HYPERplastic marrow

Question 5

Describe the major cytogenetic abnormalities associated with myelodysplastic syndromes?

Answer 5

• Partial or total loss of long arm of chromosomes 5 or 7 and 20
• Inversion of chromosome 16
• Trisomy 8

Question 6

Which gene mutation is strongly associatd with sideroblastic anemia?

Answer 6

Mutations in genes of RNA splicing machinery, especially SF3B1

Question 7

What is the clinical presentation like for myelodysplastic syndromes?

Answer 7

• Half are asymptomatic
• Sx’s may include: fatigue, pallor, bleeding and infection due to pancytopenia

Question 8

What are 2 lab abnormalities which may be seen in association with myelodysplastic syndromes?

Answer 8

• Elevated serum LDH
• Evidence (in some) of iron overload: ↑ ferritin w/ serum iron and TIBC often normal

Question 9

What are 3 differential diagnoses that should be offered up in any patient with pancytopenia?

Answer 9

• Hypersplenism
• Aplastic anemia
• Myelodysplasia

Question 10

Which myelodysplastic syndrome is associated with the lowest risk of conversion to AML (10-15%)?

Answer 10

Refractory anemia with ringed sideroblasts (RARS)

Question 11

What test and potential therapy should be done on any patient with anemia and ringed sideroblasts present?

Answer 11

• Check B₆ level (pyridoxine)
• Replace B₆ for at least 6 months if deficientm then repeat marrow - if no improvement, pt. has pyridoxine resistant sideroblastic anemia (RARS)

Question 12

What are 5 adverse prognostic features associated with Myelodysplatic Syndromes (blasts, platelets, Hgb, neutrophils, and age)?

Answer 12

• Marrow blasts >5%
• Platelets <100,000/uL
• Hemoglobin <10 g/dL
• Neutrophils <2500/uL
• Age >60 years

Question 13

List 3 cytogenetic related abnormalities associated with poor prognosis in myelodysplastic syndromes?

Answer 13

• Monosomy 7
• HYPOdiploidy
• Multiple abnormalities

Question 14

Myelodysplastic syndromes associated with what cytogenetic abnormality is associated with a favorable prognosis?

Answer 14

5q- syndrome; which leads to heterozygous loss of a ribosomal protein gene (ribosomal protein gene mutations cause Diamond-Blackfin anemia)

Question 15

What is considered supportive care for myelodysplastic syndromes, when are PRBCs and platelets given?

Answer 15

• Avoid meds that damage marrow
• Aggressive tx of infections w/ Abx
• Transfuse PRBCs when symptomatic
• Transfuse platelets ONLY for bleeding or in prep for surgery
• Watch for iron-overload; give desferrioxamine or deferasirox if present

Question 16

What is the benefit of giving EPO to pt with myelodysplastic syndromes and what level of EPO predicts poor prognosis?

Answer 16

• May decrease or ameliorate transfusion requirement in some; but is expensive
• Serum EPO level >500 predicts poor response

Question 17

Which chemotherapy drug is given for 5q- syndrome (MDS) only; what is its main MOA, and what are toxicities associated with it?

Answer 17

• Lenalidomide, an angiogenesis inhibitor; particularly effective in reversing anemia
• Toxicities = myelosuppression + ↑ risk of DVT’s and PE’s

Question 18

Which 2 chemotherapeutic agents are frequently used in high-risk MDS patients who are not candidates for stem cell transplant, and may also be effective in lower risk patients?

Answer 18

Hypomethylating agents –> Decitabine and Azacitidine

Question 19

What is the MOA of Azacitidine and Decitabine used in some pt’s with MDS; what are the major AE’s?

Answer 19

• Cause hypomethylation (demethylation) of DNA and direct cytotoxicity on abnormal bone marrow hematopoietic cells
• Major toxicity = myelosuppression, leading to worsening blood counts

Question 20

What is the only treatment which offers a cure for MDS and whom should it be considered for?

Answer 20

• Hematopoietic stem cell transplantation
• Should be considered for pt’s with MDS who are <60 and have an HLA-matching sibling donor

Question 21

ATG, cyclosporine, and the anti-CD52 monoclonal antibody alemtuzumab are especially effective in which pt’s with MDS?

Answer 21

Younger pt’s (<60) with more favorable IPSS scores and who bear HLA-DR15

Question 22

What are common presenting signs/sx’s of Primary Myelofibrosis?

Answer 22

• Anemia
• May have fever + night sweats + anorexia and weight loss
• Splenomegaly may be massive (due to ↑ extramedulary hematopoiesis)

Question 23

What is the triad of Myelofibrosis?

Answer 23

• Leukoerythroblastic anemia
• Pokilocytosis = varying shapes i.e., tear-drop cells
• Splenomegaly

Question 24

How is the diagnosis of primary myelofibrosis made and what is seen?

Answer 24

• Bone marrow biopsy
• Shows ↑ collagen and reticulin fibrosis + ↑ numbers dysplastic-appearing megakaryocytes + osteosclerosis

Question 25

What are 2 conditions that cause 2' bone marrow fibrosis which need to be excluded before making dx of primary myelofibrosis?

Answer 25

**Miliary tuberculosis** and **metastatic cancer**

Question 26

What are 3 driver mutations which may be present and assist in the dx of primary myelofibrosis; which may have better prognosis?

Answer 26

- ***JAK2* V617F** mutations in about **50%** of cases - **Calreticulin (*CALR)* mutations**: may have **better** prognosis - ***MPL* mutations**

Question 27

What are the leukocyte and platelet counts seen with Primary Myelofibrosis?

Answer 27

**Normal** or **increased**

Question 28

What are some of the complications which may arise with exuberant extramedullary hematopoiesis seen in Primary Myelofibrosis?

Answer 28

- **Portal, pulmonary**, or **intracranial HTN** - **Intestinal** or **ureteral obstruction** - **Pericardial tamponade** - **Spinal cord compression** - **Skin nodules** - **Massive splenomegaly** ---\> **splenic infarction**

Question 29

How should the anemia be managed in patient with primary myelofibrosis?

Answer 29

- Manage with **transfusion** - **EPO** administration if serum EPO **\<500** - **Transfuse platelets** ONLY if **bleed occurs**

Question 30

What is the most common cause of death in pt's with Myelofibrosis and how does this impact your treatment plan?

Answer 30

**Overwhelming infection**, so treat infections **aggressively**

Question 31

How should asymptomatic pt with primary myelofibrosis be managed?

Answer 31

**Observation**

Question 32

What are the tx options for the splenomegaly seen with primary myelofibrosis; what are the risks?

Answer 32

- **Hydroxyurea** is **variably effective** - may be **overly myelosuppressive** - Splenic **ir****radiation****-**but assoc. w/ significant risk of**neutropenia**, infection, and operative hemorrhage if splenectomy is attempted - **Splenectomy** in **severe cases** but is dangerous

Question 33

Which drug has proved effective in reducing the splenomegaly and alleviating constitutional sx's in cases of intermediate and high-risk myelofibrosis?

Answer 33

**JAK2 inhibitor, Ruxolitinib**

Question 34

What is the only curative treatment for myelofibrosis and who is it reserved for?

Answer 34

**Allogenic BM transplantation**; used in **younger** pt's and **older** pt's with **high-risk disease**

Question 35

What are some of the common and unique presenting sx's of Polycythemia Vera?

Answer 35

- **Facial rubor** = red facies - **Pruritus** with a **hot shower** or **bath** - **HA + dizziness + blurred vision** - **Heaviness** in the **arms** or **legs** - **Erythromelalgia**

Question 36

What are the laboratory findings indicative of polycythemia vera?

Answer 36

- **Increased RBC numbers** (**Hgb/Hct**): may seen **nucleated RBCs** on smear - ↑ **leukocyte alkaline phosphatase (LAP)** - ↑ **WBC** and/or **platelet** counts

Question 37

Virtually all cases of polycythemia vera are associated with what mutation?***JAK***

Answer 37

***JAK2* mutation**

Question 38

What are some of the complications which may arise with polycythemia vera?

Answer 38

- **Increased** risk of **thromboembolic** and **hemorrhagic** disorder, including **stroke** and **MI** - Associated with **Budd-Chiari Syndrome**

Question 39

What are some of the secondary causes of elevated RBC counts which need to be excluded before making dx of polycythemia vera?

Answer 39

- **Hemoconcentration** due to **dehydration**; check BUN/Cr levels - **Pulmonary disease**: COPD (smokers **polycythemia**) - **EPO producing tumors** (RCC and neuroendocrine tumors) - **Hemoglobinopathy** w/ **high affinity Hgb** - **Living** at **high altitudes**: hypoxia from decreased **FiO₂**

Question 40

What should to work-up for suspected polycythemia vera include?

Answer 40

- Full **hx** and **physical exam** - **Routine CBC** and **biochemical profile** - Exclusion of **hemoconcentration**: is pt dehydrated? BUN/Cr normal? - Check serum **EPO** level: should be **decreased** **or** **normal** in PCV - **U/S** of **kidneys** optional; but should be done if **RCC** suspected - Exclude **abnormal lung function**: pulse oximetry w/ ABG - **PFT** w/ **DLCO**: tests lung function and performance

Question 41

What is the mainstay of treatment for polycythemia vera?

Answer 41

- **Phlebotomy** of **250-500cc** whole blood every **1-2 weeks** as long as Hct \>50% - Schedule phlebotomy **chronically** for pt's **as needed** (usually every 6-12 weeks)

Question 42

Pt's with polycythemia vera who are \>60 y/o or who have had prior thromboembolic events remain at high risk for mobiditiy despite phlebotomy and should receive what treatment?

Answer 42

**Hydroxyurea**