2005 i3 dln myelodysplastic syndromes and myeloproliferative disorders jaya v.juturi md 4/24/08
TRANSCRIPT
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MYELODYSPLASTIC SYNDROMES MYELODYSPLASTIC SYNDROMES AND MYELOPROLIFERATIVE AND MYELOPROLIFERATIVE
DISORDERSDISORDERS
Jaya V.Juturi MDJaya V.Juturi MD4/24/084/24/08
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OBJECTIVESOBJECTIVES
CASECASE
DEFINITIONDEFINITION
EPIDEMIOLOGYEPIDEMIOLOGY
OVERLAP SYNDROMESOVERLAP SYNDROMES
CLASSIFICATIONCLASSIFICATION
IPSS IPSS
GOALS OF THERAPYGOALS OF THERAPY
TREATMENT OVERVIEWTREATMENT OVERVIEW
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Pathologic Classification of MDS:Pathologic Classification of MDS:FAB vs WHOFAB vs WHO
FAB Classification of MDS WHO MDS Classification
Refractory anemia (RA) RA Refractory cytopenias with multilineage
dysplasia (RCMD) MDS-unclassified (MDS-U) MDS with isolated del(5q)
Refractory anemia with ringedsideroblasts (RARS)
RARS RCMD with ringed sideroblasts (RCMD-
RS)
Refractory anemia with excess blasts (RAEB)
RAEB—Type 1 (RAEB-1) RAEB—Type 2 (RAEB-2)
Chronic myelomonocytic leukemia (CMML) MDS/myeloproliferative disorders (MPD)
RAEB-in-transformation AML
Vardiman JW, et al. Blood 2002;100:2292-2302.
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IPSS Risk Score: IPSS Risk Score: De NovoDe Novo MDS MDS
VariableWeighted Score
0 0.5 1.0 1.5 2.0
Marrow blasts, % < 5 5-10 -- 11-20 21-30
Karyotype* Good Int Poor
Cytopenias,† n 0-1 2-3
Risk Group Weighted Score
Low 0
Intermediate-1 0.5-1
Intermediate-2 1.5-2
High > 2.5
Greenberg P, et al. Blood. 1997;89:2079-2088.
*Good: normal, del 5q, del 20q, -Y; intermediate: other; poor: complex (> 3 abnormalities), chromosome 7 abnormalities
†Cytopenias: Hb < 10 g/dL, platelets < 100,000/µL, neutrophils < 1800/µL
2006 i3 dlnCopyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Fukumoto, J. et al. ASH Image Bank 2006;2006:6-00022
Figure 1. Ringed sideroblast, myelodysplastic syndromes (MDS), shown with a Prussian blue stain at low power
2006 i3 dlnCopyright ©2006 American Society of Hematology. Copyright restrictions may apply.
Fukumoto, J. et al. ASH Image Bank 2006;2006:6-00022
Figure 2. Ringed sideroblasts, myelodysplastic syndromes (MDS), shown with a Prussian blue stain at high power
2006 i3 dlnCopyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2004;2004:101041
Figure 2. Myeloid maturation is arrested
2006 i3 dlnCopyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2005;2005:101389
Figure 1. Pictured is a blast from a patient with AML
2006 i3 dlnCopyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2005;2005:101341
Figure 1. Auer rods are distinctive cytoplasmic inclusion bodies which are found in MDS and AML
2006 i3 dlnCopyright ©2005 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2005;2005:101341
Figure 2. Myeloid blast with an auer rod
2006 i3 dlnCopyright ©2004 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2004;2004:101177
Figure 5. In the peripheral blood, some of the myeloid blasts appear with prominent nucleoli
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Goals of MDS TherapyGoals of MDS Therapy
Select best treatmentSelect best treatment– Response according to predictive variablesResponse according to predictive variables– Consider type and severity of cytopenia(s), Consider type and severity of cytopenia(s),
age, and possible comorbiditiesage, and possible comorbidities IPSS intermediate-1/low riskIPSS intermediate-1/low risk
– Improve blood counts, quality of life; Improve blood counts, quality of life; decrease infectionsdecrease infections
– Decrease transfusion requirement, Decrease transfusion requirement, potentially improve survivalpotentially improve survival
Intermediate-2/high-risk IPSSIntermediate-2/high-risk IPSS– Prolong survival, delay progression to AMLProlong survival, delay progression to AML
Cheson BD, et al. Blood. 2000;96:3671-3674.MDS Guidelines. Available at: http:// www.NCCN.org.
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Myeloproliferative disordersMyeloproliferative disorders
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OBJECTIVESOBJECTIVES
DEFINITIONDEFINITION
CLASSIFICATIONCLASSIFICATION
OVERLAP SYNDROMESOVERLAP SYNDROMES
BIOLOGYBIOLOGY
CMLCML
P.VERAP.VERA
ETET
MFMF
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Myeloproliferative disordersMyeloproliferative disorders
Clonal haematopoeitic disordersClonal haematopoeitic disorders
Proliferation of one of myeloid lineagesProliferation of one of myeloid lineages
– GranulocyticGranulocytic
– ErythroidErythroid
– MegakaryocyticMegakaryocytic
Relatively normal maturationRelatively normal maturation
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Myeloproliferative disordersMyeloproliferative disordersCh Myeloid leukemia (Ch Myeloid leukemia (BCR-ABL positive)BCR-ABL positive)
Polycythemia VeraPolycythemia Vera
Essential ThrombocythemiaEssential Thrombocythemia
MyelofibrosisMyelofibrosis– Specific clincopathologic criteria for diagnosis and Specific clincopathologic criteria for diagnosis and
distinct diseases, have common featuresdistinct diseases, have common features
– Increased number of one or more myeloid cell linesIncreased number of one or more myeloid cell lines
– HepatosplenomegalyHepatosplenomegaly
– HypercatabolismHypercatabolism
– Clonal marrow hyperplasia without dysplasiaClonal marrow hyperplasia without dysplasia
– Predisposition to evolvePredisposition to evolve
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Myeloproliferative disordersMyeloproliferative disorders
MPD•PRV•ET•MF
AML
MDS•RA•RARS•RAEB I•RAEB
II
CMML
CML
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Bone marrow stem cellClonal
abnormality
Granulocyte precursors
Red cell precursors
Megakaryocytes Reactive fibrosis
Essentialthrombocytosis
(ET)
Polycythemia rubra vera
(PRV)
Myelofibrosis
AML
Chronic myeloid leukemia
70%10% 10%
30%
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Understanding of biology (JAK-2 gene)Understanding of biology (JAK-2 gene)
JAK-2 is a tyrosine kinase (cytoplasmic) critical for the JAK-2 is a tyrosine kinase (cytoplasmic) critical for the initiation of the intracellular signalling by the receptors initiation of the intracellular signalling by the receptors for erythropoietin, thrombopoietin, IL-3, G-CSF and GM-for erythropoietin, thrombopoietin, IL-3, G-CSF and GM-CSFCSF
Substitution of phenyl-alanine for Valine at position 617 Substitution of phenyl-alanine for Valine at position 617 of the JAK protein (V617F)of the JAK protein (V617F)
This is the patho-physiology of cytokine independent This is the patho-physiology of cytokine independent activation of the JAK-STAT, AKT, PI3 K pathways as well activation of the JAK-STAT, AKT, PI3 K pathways as well as the MAP-K and ERK pathwayas the MAP-K and ERK pathway
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Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Role of JAK2 in Pathway Signaling and Erythropoietin Binding, Stem-Cell Differentiation, and Development of Homozygosity for the V617F Mutation
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Incidence of the JAK-2 V617F Incidence of the JAK-2 V617F mutationmutation
65-95% patients with P.Vera65-95% patients with P.Vera
50% patients with myelofibrosis50% patients with myelofibrosis
25-60% patients with essential 25-60% patients with essential thrombocythemiathrombocythemia
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Campbell P and Green A. N Engl J Med 2006;355:2452-2466
Classification of the Myeloproliferative Disorders on the Basis of Molecular Pathogenetic Characteristics
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Epidemiology of CMLEpidemiology of CML
Median age range at presentation: 45 to 55 yearsMedian age range at presentation: 45 to 55 years
• 12% - 30% of patients are >60 years old12% - 30% of patients are >60 years old
At presentationAt presentation
– 50% diagnosed by routine laboratory tests50% diagnosed by routine laboratory tests
– 85% diagnosed during chronic phase85% diagnosed during chronic phase
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Presentation
Insidious onset
Anorexia and weight loss
Symptoms of anemia
Splenomegaly –maybe massive
Pt . maybe asymptomatic
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The Philadelphia Chromosome: t(9;22) The Philadelphia Chromosome: t(9;22) TranslocationTranslocation
bcr-abl
Fusion proteinwith tyrosine
kinase activity
22
bcr
abl
Ph
9 9+
Philadelphia chromosome
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2006 i3 dlnCopyright ©2002 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2002;2002:100445
Figure 1. Numerous platelets are noted in the peipheral blood smear from a patient with CML
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Clinical Course: Phases of CMLClinical Course: Phases of CML
Chronic phase
Median 4–6 yearsstabilization
Accelerated phase
Median durationup to 1 year
Blastic phase (blast crisis)
Median survival3–6 months
Terminal phase
Advanced phases
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Treatment of Chronic Myeloid leukemia
Arsenic Lissauer, 1865
Radiotherapy Pusey, 1902
Busulfan Galton, 1953
Hydroxyurea Fishbein et al, 1964
Autografting Buckner et al, 1974
Allogeneic BMT (SD) Doney et al, 1978
Interferon Talpaz et al, 1983
Allogeneic BMT (UD) Beatty et al, 1989
Donor Leukocytes Kolb et al, 1990
Imatinib Druker et al, 1998
Imatinib/Combination therapy O’Brien et al, 200……
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The Ideal Target for Molecular TherapyThe Ideal Target for Molecular Therapy
Present in the majority of patients with a Present in the majority of patients with a specific diseasespecific disease
Determined to be the causative abnormalityDetermined to be the causative abnormality
Has unique activity that isHas unique activity that is
- Required for disease induction- Required for disease induction
- Dispensable for normal cellular function- Dispensable for normal cellular function
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Mechanism of Action of ImatinibMechanism of Action of Imatinib
Goldman JM. Lancet. 2000;355:1031-1032.
Bcr-Abl
ATP
Substrate
Imatinib
Y = TyrosineP = Phosphate
Bcr-Abl
Substrate
PPP
P
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O'Brien S et al. N Engl J Med 2003;348:994-1004
Kaplan-Meier Estimate of the Time to a Major Cytogenetic Response
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CMLCML
Diagnosis
Young with a well-matched donor
Start Imatinib at400mg/day
Cosider for Allograft
Allo SCT
Poor response or Initial response
Followed byLoss of response
Add or substituteOther agents
Allo-SCTAuto
Good response maintained
Continue Imatinib indefinitely
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Issues related to Imatinib
• Very few molecular responses (5-10%)
• Resistance in some patients
• Lack of response in some patients
• Expensive
• Long term toxicity/side effects unknown
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PolycythemiaPolycythemia
True / AbsoluteTrue / Absolute
– Primary PolycythemiaPrimary Polycythemia
– Secondary PolycythemiaSecondary Polycythemia• Epo dependentEpo dependent– Hypoxia dependentHypoxia dependent– Hypoxia independentHypoxia independent
• Epo independentEpo independent
Apparent / RelativeApparent / Relative
– Reduction in plasma volumeReduction in plasma volume
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Causes of secondary polycythemiaCauses of secondary polycythemia ERYTHROPOIETIN (EPO)-MEDIATEDERYTHROPOIETIN (EPO)-MEDIATED
– Hypoxia-DrivenHypoxia-Driven• Chronic lung diseaseChronic lung disease• Right-to-left cardiopulmonary vascular shuntsRight-to-left cardiopulmonary vascular shunts• High-altitude habitatHigh-altitude habitat• Chronic carbon monoxide exposure (e.g., smoking)Chronic carbon monoxide exposure (e.g., smoking)• Hypoventilation syndromes including sleep apneaHypoventilation syndromes including sleep apnea• Renal artery stenosis or an equivalent renal pathologyRenal artery stenosis or an equivalent renal pathology
– Hypoxia-Independent (Pathologic EPO Production)Hypoxia-Independent (Pathologic EPO Production)• Malignant tumorsMalignant tumors
– Hepatocellular carcinomaHepatocellular carcinoma– Renal cell cancerRenal cell cancer– Cerebellar hemangioblastomaCerebellar hemangioblastoma
• Nonmalignant conditionsNonmalignant conditions– Uterine leiomyomasUterine leiomyomas– Renal cystsRenal cysts– Postrenal transplantationPostrenal transplantation– Adrenal tumorsAdrenal tumors
DRUG-ASSOCIATEDDRUG-ASSOCIATED– EPO DopingEPO Doping– Treatment with Androgen PreparationsTreatment with Androgen Preparations
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POLYCYTHEMIA VERAPOLYCYTHEMIA VERAChronic, clonal myeloproliferative disorder Chronic, clonal myeloproliferative disorder
characterized by an absolute increase in characterized by an absolute increase in number of RBCsnumber of RBCs
2-3 / 1000002-3 / 100000
Median age at presentation: 55-60Median age at presentation: 55-60
M/F: 0.8:1.2 M/F: 0.8:1.2
Hct > 60% for men and 56% for women in Hct > 60% for men and 56% for women in the absence of secondary causesthe absence of secondary causes
65-95% with a JAK-2 (V617F) mutation65-95% with a JAK-2 (V617F) mutation
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Clinical featuresClinical features
Headache, pruritus, dyspnea, blurred vision, facial Headache, pruritus, dyspnea, blurred vision, facial
plethoraplethora
Persistent leukocytosis and or thrombocytosisPersistent leukocytosis and or thrombocytosis
Microcytosis secondary to iron deficiencyMicrocytosis secondary to iron deficiency
SplenomegalySplenomegaly
Unusual thrombosis (e.g., Budd-Chiari syndrome)Unusual thrombosis (e.g., Budd-Chiari syndrome)
Erythromelalgia (acral dysesthesia and erythema)Erythromelalgia (acral dysesthesia and erythema)
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WHO--Diagnostic CriteriaWHO--Diagnostic CriteriaA1A1 Raised red cell mass hgb>18.5 in men or Raised red cell mass hgb>18.5 in men or
>16.6g/dl in women>16.6g/dl in women
A2A2 Normal O2 sats and EPONormal O2 sats and EPO
A3A3 Palpable spleen Palpable spleen
A4A4 No BCR-ABL fusionNo BCR-ABL fusion
B1B1 Thrombocytosis >400 x 109/LThrombocytosis >400 x 109/L
B2B2 Hyper cellular Bone marrow Hyper cellular Bone marrow
B3B3 Neutrophilia >12 x 10 Neutrophilia >12 x 1099/L/L
B4B4 Low serum EPO levelsLow serum EPO levels
A1+A2+either another A or two B establishes PVA1+A2+either another A or two B establishes PV
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TreatmentTreatment The mainstay of therapy in PV remains phlebotomy to keep the The mainstay of therapy in PV remains phlebotomy to keep the
hematocrit below 45 percent in men and 42 percent in womenhematocrit below 45 percent in men and 42 percent in women
Additional hydroxyurea in high-risk pts for thrombosis (age over Additional hydroxyurea in high-risk pts for thrombosis (age over 70, prior thrombosis, platelet count >400,000/microL, presence of 70, prior thrombosis, platelet count >400,000/microL, presence of cardiovascular risk factors)cardiovascular risk factors)
Aspirin (75-100 mg/d) if no contraindication, reduces thrombosesAspirin (75-100 mg/d) if no contraindication, reduces thromboses
IFNa (3mu three times per week) in patients with refractory IFNa (3mu three times per week) in patients with refractory pruritus, pregnancypruritus, pregnancy
Normalize hematocrit values for several days prior to any elective Normalize hematocrit values for several days prior to any elective surgerysurgery
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Landolfi R et al. N Engl J Med 2004;350:114-124
Probability of Survival Free of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes (Panel A) and Probability of Survival Free of Myocardial Infarction, Stroke, Death from
Cardiovascular Causes, Pulmonary Embolism, and Deep Venous Thrombosis (Panel B)
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Essential Thrombocythemia (ET)Essential Thrombocythemia (ET)
Most common clonal MPDMost common clonal MPD
Persistent elevation of Plt>600 /microLPersistent elevation of Plt>600 /microL
Lack of positive diagnostic criteriaLack of positive diagnostic criteria
Median age at diagnosis: 60, however 20% cases <40yrsMedian age at diagnosis: 60, however 20% cases <40yrs
JAK-2 mtation found upto 50% of the ptsJAK-2 mtation found upto 50% of the pts
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Clinical FeaturesClinical Features VasomotorVasomotor
– Headache Headache
– Lightheadedness Lightheadedness
– Syncope Syncope
– Erythromelalgia (burning pain of the hands or feet Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) associated with erythema and warmth)
– Transient visual disturbances (eg, amaurosis fujax, Transient visual disturbances (eg, amaurosis fujax, scintillating scotomata, ocular migraine) scintillating scotomata, ocular migraine)
– Livedo reticularisLivedo reticularis
Thrombosis and HemorrhageThrombosis and Hemorrhage
Transformation rareTransformation rare
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InvestigationsInvestigationsET is a diagnosis of exclusionET is a diagnosis of exclusion
Rule out other causes of elevated platelet countRule out other causes of elevated platelet count
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Diagnostic criteria for ETDiagnostic criteria for ET Platelet count >600 x 109/L for at least 2 months Platelet count >600 x 109/L for at least 2 months
Megakaryocytic hyperplasia on bone marrow Megakaryocytic hyperplasia on bone marrow aspiration and biopsy aspiration and biopsy
No cause for reactive thrombocytosisNo cause for reactive thrombocytosis
Absence of the Philadelphia chromosomeAbsence of the Philadelphia chromosome
Normal red blood cell (RBC) mass or a HCT <0.48Normal red blood cell (RBC) mass or a HCT <0.48
Presence of stainable iron in a bone marrow aspiration Presence of stainable iron in a bone marrow aspiration
No evidence of myelofibrosisNo evidence of myelofibrosis
No evidence of MDSNo evidence of MDS
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Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia
Hydroxyurea plus low-dose aspirin is superior Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for with essential thrombocythemia at high risk for vascular events. vascular events.
N Engl J Med 2005; 353:33-45
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Harrison C et al. N Engl J Med 2005;353:33-45
Kaplan-Meier Estimates of Survival Free of the Primary End Point of Arterial or Venous Thrombosis, Serious Hemorrhage, or Death from Any of These Causes
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Therapy of ET based on the risk of Therapy of ET based on the risk of thrombosisthrombosis
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Myelofibrosis with myeloid Myelofibrosis with myeloid metaplasiametaplasia
Clonal abnormal hematopoietic stem cells that release fibrosis Clonal abnormal hematopoietic stem cells that release fibrosis promoting cytokines in the bone marrowpromoting cytokines in the bone marrow
Splenomegaly and Hepatomegaly (extramedullary Splenomegaly and Hepatomegaly (extramedullary hematopoiesis)hematopoiesis)
Leukoerythroblastic picture, Teardrop cellsLeukoerythroblastic picture, Teardrop cells
Median survival is 3-5 yearsMedian survival is 3-5 years
Death from marrow failure, transformation or complications of Death from marrow failure, transformation or complications of portal HTNportal HTN
Low dose thalidomide with or without steroids, Allogenic Low dose thalidomide with or without steroids, Allogenic transplant in young patientstransplant in young patients
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2006 i3 dlnCopyright ©2003 American Society of Hematology. Copyright restrictions may apply.
Maslak, P. ASH Image Bank 2003;2003:100839
Figure 1. Blasts are increased in this bone marrow aspirate
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CaseCase
50 year old man with pruritus while showering50 year old man with pruritus while showering
Otherwise excellent state of healthOtherwise excellent state of health
Non smoker and a palpable spleen tip on examNon smoker and a palpable spleen tip on exam
FOB screen negative, normal O2 satFOB screen negative, normal O2 sat
Hct 61%, wbc 11k, MCV 79, Plt count 550, Hct 61%, wbc 11k, MCV 79, Plt count 550, ferritin 12, GI screen Okayferritin 12, GI screen Okay
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Most appropriate therapyMost appropriate therapy
Phlebotomy and anagrelidePhlebotomy and anagrelide
Oral iron and AsaOral iron and Asa
Hydroxyurea and asaHydroxyurea and asa
Phlebotomy and low dose asaPhlebotomy and low dose asa
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CaseCase
56 year old male with fatigue, fever and nose 56 year old male with fatigue, fever and nose bleedsbleeds
RAEB-1 diagnosed 5 months agoRAEB-1 diagnosed 5 months ago
Supportive care with PRBC’s and EPO to dateSupportive care with PRBC’s and EPO to date
Fever 103 F, ecchymoses and petechiae, no Fever 103 F, ecchymoses and petechiae, no organomegaly or adenopathyorganomegaly or adenopathy
HgB 6 wbc 1.2, plts 7KHgB 6 wbc 1.2, plts 7K
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In addition to a transfusion and a bone marrow In addition to a transfusion and a bone marrow aspirateaspirate
Plasma exchangePlasma exchange
Allogeneic stem cell transplantAllogeneic stem cell transplant
AzacytidineAzacytidine
Combination induction chemotherapyCombination induction chemotherapy
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CaseCase
76 year old man with extreme fatigue, dyspnea, 76 year old man with extreme fatigue, dyspnea, early satiety and night sweatsearly satiety and night sweats
Lost 10% of baseline weightLost 10% of baseline weight
large spleen, HgB 7.6, WBC 4.2, plts 1.2 Mlarge spleen, HgB 7.6, WBC 4.2, plts 1.2 M
Bone marrow “dry tap”, PH chromosome negBone marrow “dry tap”, PH chromosome neg
Improves with a transfusionImproves with a transfusion
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OPTIONSOPTIONS
Chronic transfusionsChronic transfusions
SplenectomySplenectomy
Daily Imatinib MesylateDaily Imatinib Mesylate
Allogeneic stem cell transplantAllogeneic stem cell transplant