Myelodysplastic Syndromes & Myeloproliferative Disorders

Question 1

Etiologic factors involved in development of myelodysplastic syndromes (MDS)

Answer 1

Mostly a disease of aging (due to chromosomal and genetic instability)

Environmental exposures — radiation, benzene

Secondary MDS associated with hx of radiation therapy and chemo (esp alkylating agents like busulfan, nitrosurea, or procarbazine, and the DNA topoisomerase inhibitors, and anthracyclines)

Germline mutations in GATA2, RUNX1, or telomere repair gene mutations

Question 2

Cytogenetic abnormalities associated with MDS

Answer 2

Loss of all or part of 5, 7, and 20

Trisomy 8

Inv16

Question 3

MDS associated with mutations of genes of splicing machinery, especially SF3B1 are associated with ____ anemia

Answer 3

Sideroblastic

Question 4

Gene mutations that correlate with poor px of MDS

Answer 4

EZH2
TP53
RUNX1
ASXL1

Monosomy 7
Hypodiploidy

Question 5

Gene mutations that correlate with favorable px of MDS

Answer 5

Spliceosome defects (5q syndrome)

Question 6

Consequences of 5q- deletion in MDS

Answer 6

5q- deletion leads to heterozygous loss of a ribosomal protein gene (ribosomal gene muations cause Diamond Blackfan anemia)

Question 7

Overall, MDS has poor px with median survival 2 years. Course may be variable. Besides gene mutations, what are some pt factors that are associated with adverse px?

Answer 7

Marrow blasts >5%

Platelets <100,000/ul

Hemoglobin <10 g/dL

Neutrophils <2500/ul

Age >60

Question 8

5q syndrome MDS has a beneficial response reported to _______

What is its MOA?

Answer 8

Lenalidomide

[Angiogenesis inhibitor for use in 5q syndrome ONLY]

Question 9

Describe low/intermediate intensity therapy options for MDS, and their MOAs

Answer 9

5-azacytadine and decitabine

MOA: cause hypomethylation of DNA and direct cytotoxicity on abnormal bone marrow hematopoeitic cells

Question 10

Major toxicities of azacitidine and decitabine

Answer 10

Myelosuppression —> worsening blood counts

Question 11

Toxicities of lenalidomide

Answer 11

Myelosuppression (worsens neutropenia and thrombocytopenia)

Increased risk of DVT and PE

Question 12

Common clinical complaints and PE findings in pts with idiopathic myelofibrosis

Answer 12

Pts present with sxs due to anemia and may have prominent systemic features such as fever, night sweats, anorexia, and weight loss.

Splenomegaly may be massive and cause abd pain and early satiety

PE reveals pallor, hepatomegaly, and dramatic splenomegaly that may extend to pelvic brim

Question 13

Peripheral smear and bone marrow bx findings with myelofibrosis

Answer 13

Myelophthisic/leukoerythroblastic on PB — immature leukocytes, nucleated erythrocytes, teardrop shaped erythrocytes

Bone marrow bx usually a dry tap — can see increased reticulin and collagen fibrosis, increased numbers of dysplastic megakaryocytes, and osteosclerosis

Question 14

Mutation found in 50% of myelofibrosis pts

Answer 14

JAK2 (V617F)

Question 15

Mutations associated with chronic (idiopathic) myelofibrosis

Answer 15

JAK2

MPL (Thrombopoietin receptor)

CLR (calreticulin gene)

Question 16

Tx plan for idiopathic myelofibrosis

Answer 16

No definitive therapy — symptom attenuation is goal

Danazol for anemia (consider transfusions)

Hydroxyurea for splenomegaly

Allopurinol for hyperuricemia/gout

Pegylated IFN-a can ameliorate fibrosis in early cases, but later exacerbates BM failure

Ruxolitinib (JAK2 inhibitor) for splenomegaly and consitutional sxs

Allogeneic BMT only curative therapy

Question 17

Common disorders known to cause secondary erythrocytosis

Answer 17

Hemoconcentration

COPD (smoker’s polycythemia)

EPO-producing tumors (RCC, neuroendocrine tumors)

Hemoglobinopathy with high affinity Hb

Living at high altitude (hypoxia from decreased FiO2)

Question 18

Common clinical complaints and PE findings in pts with polycythemia vera

Answer 18

Present with vague nonspecific sxs like HA or malaise

Less commonly pruritis w/skin or liver disease; may also have erythromelalgia

Complications =thromboembolic events

PE findings — plethora, HSM

Question 19

Virtually all pts with PCV have a mutation in ____

Answer 19

JAK2

Question 20

Usual lab findings with polycythemia vera

Answer 20

Erythrocytosis, often with leukocytosis and thrombocytosis

Elevated LAP score

Increased bands and myelocytes, as well as increased eosinophils and basophils

Low erythropoietin levels

Bone marrow exam = hypercellularity w/left shift

Question 21

Tx plan for polycythemia vera

Answer 21

Therapeutic phlebotomy

Pts with prior thromboembolic events should receive a myelosuppressive agent such as hydroxyurea

Stroke prevention — BP control, smoking cessation, hyperlipidemia management

Question 22

Secondary causes of erythrocytosis include: Hemoconcentration

COPD (smoker’s polycythemia)

EPO-producing tumors (RCC, neuroendocrine tumors)

Hemoglobinopathy with high affinity Hb

Living at high altitude (hypoxia from decreased FiO2)

—How would these be differentiated from polycythemia vera?

Answer 22

Exclude abnl lung function w/pulse ox and ABG (smokers have elevated carboxyhemoglobin); also PFT with DLCO

Also if JAK2 mutation is present along with normal serum EPO level, that identifies 98% of pts with P.vera

Question 23

Refractory anemia with ringed sideroblasts (RARS) will show ringed sideroblasts in marrow precursors. Some patients with anemia are found to have these ringed sideroblasts on marrow exam secondary to _____ deficiency; thus this lab must be checked on every pt with ringed sideroblasts!

Answer 23

B6 (pyridoxine)

— if B6 deficient, replace their B6 x6 months then repeat marrow, if no improvement then they have RARS

Question 24

70 y/o M c/o fatigue and recurrent infections. He has a 4 lb weight loss in the last 2 months and evience of increased bruising. He takes baby ASA daily for stroke prevention. The most helpful test for his symptoms is

A. CXR
B. CBC
C. CMP
D. Urinalysis
E. Platelet aggregation test

Answer 24

B. CBC

Question 25

70 y/o M c/o fatigue and recurrent infections. He has a 4 lb weight loss in the last 2 months and evience of increased bruising. He takes baby ASA daily for stroke prevention. CBC shows WBC 2.8, Hb 10.1, and platelet count of 104K. The most helpful test to evaluate his sxs is

A. Pulmonary function study
B. Platelet aggregation test
C. Hepatitis serologies
D. Bone marrow exam
E. Urine creatinine clearance

Answer 25

D. Bone marrow exam

[all 3 cell lines affected; would also look at PB smear]

Question 26

70 y/o M c/o fatigue and recurrent infections. He has a 4 lb weight loss in the last 2 months and evience of increased bruising. He takes baby ASA daily for stroke prevention. CBC shows WBC 2.8, Hb 10.1, and platelet count of 104K. Marrow exam shows refractory anemia with a few ringed sideroblasts. The next step in tx is:

A. Trial of pyridoxine
B. Vit B6 level
C. Course of decitabine
D. Course of lenalidomide
E. Multivitamin w/iron

Answer 26

B. Vit B6 level

Question 27

90 y/o F presents to discuss recent CBC that showed WBC 12,000 with increase in monocytes. Absolute monocyte count is 1250/cc. Hb and plts are normal. She is asymptomatic, has dementia, and lives with her son. You are most concerned about

A. AML
B. CMML
C. PRV
D. Myelofibrosis
E. Pyelonephritis

Answer 27

B. CMML

Question 28

90 y/o F presents to discuss recent CBC that showed WBC 12,000 with increase in monocytes. Absolute monocyte count is 1250/cc. Hb and plts are normal. She is asymptomatic, has dementia, and lives with her son. The best method to evaluate this process is:

A. Serum B12 and folate levels
B. Bone marrow exam
C. CRP level
D. CT scanning of abdomen
E. Blood and urine cultures

Answer 28

B. Bone marrow exam

Question 29

Triad of myelofibrosis

Answer 29

Leukoerythroblastic anemia

Poikilocytosis

Splenomegaly