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Toronto Notes 2019 Myeloproliferative Neoplasms
Investigations
• CBC:anemia,variableplatelets,variableWBC
• biochemistry:increasedALP(liverinvolvement,bonedisease),increasedLDH(2otoineffective
hematopoiesis), increased uric acid (increased cell turnover), increased B12 (2o to increased neutrophil
mass)
• bloodfilm:leukoerythroblastosiswithteardropRBCs,nucleatedRBCs,variablepolychromasia,large
platelets, and megakaryocyte fragments
• JAK2 PCR and calreticulin PCR
• bone marrow aspirate: “dry tap” in as many as 50% of patients (no blood cells aspirated)
• bonemarrowbiopsy(essentialfordiagnosis):fibrosis,atypicalmegakaryocytichyperplasia,thickening
and distortion of the bony trabeculae (osteosclerosis)
Treatment
• allogeneicstemcelltransplantispotentiallycurative • JAK2inhibitors(Ruxolitinib)
• symptomatictreatment
■ transfusion for anemia
■ erythropoietin: 30-50% of patients respond
■ androgens for anemia (e.g. danazol has shown transient response with response rates of <30%) ■ hydroxyurea for splenomegaly, thrombocytosis, leukocytosis, and systemic symptoms
◆ interferon-α (as second line therapy)
◆ splenectomy (as third line therapy; associated with high mortality and morbidity)
■ radiation therapy for symptomatic extramedullary hematopoiesis, and symptomatic splenomegaly
Prognosis
• DynamicInternationalPrognosticScoringSystem(DIPSS)PlusforIMFuses5riskfactorsalongwith karyotype, platelet count, and transfusion status to predict survival
■ presence of constitutional symptoms; age >65; hemoglobin <100 g/L; leukocyte count >25,000/mm3; circulating blast cells ≥1%
■ based on the calculated score, a patient’s IMF is categorized as “low”, “intermediate 1”, “intermediate 2”, or “high” with a mean survival of 185, 78, 35, and 16 mo, respectively
• riskoftransformationtoAML(8-10%)
Essential Thrombocythemia
Definition
• overproductionofplateletsintheabsenceofrecognizablestimulus • mustruleoutsecondarythrombocythemia
Epidemiology
• increaseswithage;F:M=2:1,butF=Matolderage
Diagnosis (2008 WHO Criteria Revised in 2016) requires meeting all four criteria
1. Sustained platelet count >450 x 109/L
2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with
increased number of enlarged, mature megakaryocytes; no significant increase or left shift of neutrophil
granulopoiesis or erythropoiesis
3. Not meeting WHO criteria for PV, primary myelofibrosis, bcr-abl CML, or myelodysplastic syndrome
or other myeloid neoplasms
4. Demonstration of JAK2 V617F, calreticulin or MPL mutation (or in its absence another clonal marker),
no evidence for reactive thrombocytosis
Clinical Features
• oftenasymptomatic
• vasomotorsymptoms(40%)
■ headache (common), dizziness, syncope
■ erythromelalgia (burning pain of hands and feet, dusky colour, usually worse with heat, caused by
platelet activation → microvascular thrombosis)
• thrombosis(arterialandvenous)
• bleeding(oftenGI;associatedwithplatelets>1,000x109/L)
• constitutionalsymptoms,splenomegaly
• pregnancycomplications;increasedriskofspontaneousabortion • riskoftransformationtoAML(0.6-5%),myelofibrosis
Investigations
• CBC:increasedplatelets;mayhaveabnormalplateletaggregationstudiesorvWDstudies • JAK2PCRassay;ifnegative,CALRPCRassay
• bonemarrowhypercellularity,megakaryocytichyperplasia,giantmegakaryocytes
• increased K+, increased PO43- (2o to release of platelet cytoplasmic contents)
• diagnosis:excludeothermyeloproliferativedisordersandreactivethrombocytosis
Treatment
• lowdoseASAifprevioushistoryofthromboticevent,≥1cardiovascularriskfactors,older,or symptomatic
• cytoreductivetherapyifthrombosisorthromboticsymptoms:hydroxyurea(HU)(1st-linetherapy), anagrelide, interferon-α, or 32P (age >80 or lifespan <10 yr)
Hematology H43
A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis
NEJM 2012;366:799-807
Study: Double-blinded RCT of 309 patients with myelofibrosis randomized to ruxolitinib or placebo. Outcome: Primary outcome was reduction in spleen volume of >35% at 24 wk. Secondary outcomes were durability of response, symptom burden, and overall survival.
Results: A greater proportion of patients on ruxolitinib had reduction in spleen volume >35% (41.9% vs. 0.7%) and this was sustained in 67% at 48 wk. Ruxolitinib also led to greater symptom improvement (45% vs. 5.3%) and less mortality (13 vs. 24). There was no difference in rate of discontinuation due to adverse events (11.0% vs. 10.6%) but anemia and thrombocytopenia were more common with ruxolitinib.
Conclusions: Ruxolitinib reduced spleen size, improved symptoms and improved survival, compared with placebo.
Etiology of Secondary Thrombocythemia
• Infection
• Inflammation (IBD, arthritis) • Malignancy
• Hemorrhage
• Iron deficiency
• Hemolytic anemia
• Post splenectomy
• Post chemotherapy
Anagrelide vs. Hydroxyurea for Essential Thrombocythemia: ANAHYDRET Study, A Randomized Controlled Trial
Blood 2013;121:1720-8
Study: Prospective, non-inferiority, RCT. Majority of patients followed beyond 1 yr.
Population: 259 previously untreated, high-risk patients with essential thrombosis as per the WHO guidelines.
Intervention: Patients were randomized to receive either non-immediate release formulation of anagrelide or hydroxyurea.
Outcome: Examined platelet counts, hemoglobin levels, leukocyte counts, and occurrence of ET- related events.
Results: The hazard ratio (HR) of developing thrombocythemia was 1.19 (95% CI 0.61-2.30). The HR for a reduction of hemoglobin was 1.03 (95% CI 0.57-1.81), and 0.92 (95% CI 0.57-1.46) for leukocytosis. There was no statistical difference
in occurrence of major or minor arterial or venous thrombosis, severe or minor bleeding events, or rate of discontinuation between the two arms. Conclusions: In patients with ET, anagrelide is non-inferior to hydroxyurea in the prevention of thrombotic complications.
There is an asymptomatic “benign” form of essential thrombocythemia with a stable
or slowly rising platelet count; treatment includes observation, ASA, sulfinpyrazone, or dipyridamole