Myelodysplastic Syndromes & Myeloproliferative Disorders Flashcards
Etiologic factors involved in development of myelodysplastic syndromes (MDS)
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
Cytogenetic abnormalities associated with MDS
Loss of all or part of 5, 7, and 20
Trisomy 8
Inv16
MDS associated with mutations of genes of splicing machinery, especially SF3B1 are associated with ____ anemia
Sideroblastic
Gene mutations that correlate with poor px of MDS
EZH2
TP53
RUNX1
ASXL1
Monosomy 7
Hypodiploidy
Gene mutations that correlate with favorable px of MDS
Spliceosome defects (5q syndrome)
Consequences of 5q- deletion in MDS
5q- deletion leads to heterozygous loss of a ribosomal protein gene (ribosomal gene muations cause Diamond Blackfan anemia)
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?
Marrow blasts >5%
Platelets <100,000/ul
Hemoglobin <10 g/dL
Neutrophils <2500/ul
Age >60
5q syndrome MDS has a beneficial response reported to _______
What is its MOA?
Lenalidomide
[Angiogenesis inhibitor for use in 5q syndrome ONLY]
Describe low/intermediate intensity therapy options for MDS, and their MOAs
5-azacytadine and decitabine
MOA: cause hypomethylation of DNA and direct cytotoxicity on abnormal bone marrow hematopoeitic cells
Major toxicities of azacitidine and decitabine
Myelosuppression —> worsening blood counts
Toxicities of lenalidomide
Myelosuppression (worsens neutropenia and thrombocytopenia)
Increased risk of DVT and PE
Common clinical complaints and PE findings in pts with idiopathic myelofibrosis
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
Peripheral smear and bone marrow bx findings with myelofibrosis
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
Mutation found in 50% of myelofibrosis pts
JAK2 (V617F)
Mutations associated with chronic (idiopathic) myelofibrosis
JAK2
MPL (Thrombopoietin receptor)
CLR (calreticulin gene)
Tx plan for idiopathic myelofibrosis
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
Common disorders known to cause secondary erythrocytosis
Hemoconcentration
COPD (smoker’s polycythemia)
EPO-producing tumors (RCC, neuroendocrine tumors)
Hemoglobinopathy with high affinity Hb
Living at high altitude (hypoxia from decreased FiO2)
Common clinical complaints and PE findings in pts with polycythemia vera
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
Virtually all pts with PCV have a mutation in ____
JAK2
Usual lab findings with polycythemia vera
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
Tx plan for polycythemia vera
Therapeutic phlebotomy
Pts with prior thromboembolic events should receive a myelosuppressive agent such as hydroxyurea
Stroke prevention — BP control, smoking cessation, hyperlipidemia management
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?
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
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!
B6 (pyridoxine)
— if B6 deficient, replace their B6 x6 months then repeat marrow, if no improvement then they have RARS
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
B. CBC
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
D. Bone marrow exam
[all 3 cell lines affected; would also look at PB smear]
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
B. Vit B6 level
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
B. CMML
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
B. Bone marrow exam
Triad of myelofibrosis
Leukoerythroblastic anemia
Poikilocytosis
Splenomegaly
