Myeloid Malignancies

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    Intro

    • Low grade neoplasms characterized by increased proliferation
      • Can be various cell lines, or stroma of bone marrow. 
    • (myelodysplastic syndromes are disordered hematopoeisis). 

     

    Polycythemia Vera

    • Typically found incidentally to have abnormally elevated RBC.
    • Age 50-75, 5% younger than 40.
    • Mutation in JAK2 --> signalling molecule --> cascade to cause transcription.
      • V617F  --> causes JAK2 to be constituently active. 
      • All patients in PV have JAK2
      • Even without EPO, cells are growing.  (grow in cultures without stimulating factors).
    • 3 Stages
      • Latent
      • Proliferative
        • (hyperviscocity, hypermetabolic, thrombosis)
        • JAK2 + elevated RBC --> increase in platelets.
      • Spent Stage (20% enter this phase)
        • Fibrosis of bone marrow (maybe due to platelet derived growth factor + signals)
        • Bone marrow becomes fibrotic, erythropoeisis moves to extra-marrow structures (liver, spleen).
          • Progressive hepatosplenomegaly.
          • Constitutional symptoms (weakness fatigue fever, etc..).
    • Symptoms
      • General:
        • Hyperviscocity (confusion)
        • TIA - like syndromes
        • Tinnitus, blurred vision, headache
      • Specific:
        • Generalized pruritis (worsens after bathing)
        • Erythromalalgia (burning sensation of palms, soles, likely d/t platelet activation) --> tx sx with ASA.
        • Hypermetabolic (fever, weight loss, sweating).
      • 20% have arterial or venous thrombosis as first symptom.
        • JAK2 is itself pro-thrombotic.
        • High risk of Budd-Chiari sindrome (Many NYD cases are JAK2 positive).
      • Bleeding  (too many platelets can cause bleeding, overcrowd).
        • Autophlebotomize --> become iron deficient but not anemic. 
      • NOTE: See high hematocrit, but cells are microcytic (iron deficient)  ---> pathognemonic for PV
    • Investigations:
      • Historically relied on red cell mass (need radioactivity, not done anymore)
      • Lab Features:
        • JAK2 V617F Mutation (>97% of PVR will have) - still possible if negative, look at other criteria
        • Erythrocytosis
        • Leukocytosis
        • Trombocytosis
        • Basophilia
        • Elevated serum uric acid
        • Elevated B12
        • Low EPO
        • Normal O2 sat
      • To diagnose PV, need:

             2 Major + 1 Minor OR  1 Major + 2 Minor

         

        • Major Criteria:
          • Hb >18.5 g/dL (185 SI) in men, >16.5 g/dL (165 SI) in women
            (or elevated red cell mass greater than 25% above mean normal predicted value)
          • JAK2 V617F
            (OR other mutations, such as the exon 12 mutation of JAK2)
        • Minor Criteria
          • Marrow bx: hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
          • Low serum EPO
          • Endogenous erythroid colony formation in vitro.
      •  
      • Secondary Causes of Erythrocytosis:
        • EPO level --> level should be undetectable.
          • If high, look for seconary causes of erythrocytosis
            • Cardiorespiratory (chronic hypoxia):
              • OSA, COPD, smoking, CO poisoning, congenital heart disease (R->L shunting), lung shunts (AV malformations).
            • Renal: RCC, renal artery stenosis.
    • Complications:
      • Can progress to AML, bleeding, thrombosis.
    • Treatment:
      • Low dose ASA (decreases risk of thrombosis) --> Give to ALL patients.
        • (Old studies used high dose ASA --> increased bleeding.  New studies use ASA 81 --> benefit).
      • Phlebotomy to target hematocrit <45% (maintenance target: 40-45%)
      • DO NOT take supplemental iron (want to be iron deficient, avoids phlebotomizing).
      • Hydroxyurea (add to phlebotomy):  [RNA reductase inhibitor]
        • Indications:
          • Thrombocytosis (phlebotomy alone cannot control thrombocytosis and HSM)
          • Age >60, History of prior thrombotic event. (Unclear if together or separate)
        • Also decreases phlebotomy need.
      • Other Therapies:
        • P32 (radioactive phosphorus)
          • popular myelosuppression, some utility in short life expectancy (increases risk of leukemia 11%)
        • Interferon alpha - treat PV in pregnancy
          • No increase risk of leukemia/thrombosis
          • Side Effects: fever, myalgia, flu-like symptoms, depression.  (20% discontinue)
      • NOTE: Phlebotomy is not a risk factor for myelofibrosis.
      • NOTE: Hydroxyurea is preferred to other myelosupressives because others are leukemiagenic. 

     

    Essential Thrombocythemia (ET)

    • Elevation of platelet count in conditions not known to cause secondary thrombocytosis.
    • Increased megakaryocyte production of platelets in normal platelet survival.
    • 50% of patients with PT also have JAK2 V617F.
    • NOTE: Thrombopoetin levels are multifactorial (platelet count, megakaryocyte mass) - not as useful as EPO.
       
    • aka Primary Thrombocytosis
    • Secondary Thrombocytosis
      • ***Iron deficiency***
      • Malignancies
      • Inflammation
      • Infection
      • Splenectomy
    • Symptoms
      • Erythromalalgia - burning in hands and feet (responds to ASA like in PV).
      • Bleeding: vWF binds to platelets and lots of platelets soaks up vWF 
      • Platelet 
    • Suspect in all patients with platelets > 600 x10^3.
    • If >1000 x10^3 --> severe! Strongly suggestive of ET (rarely secondary).
    • Diagnosis:
      • Diagnosis of ET:

              1.  Platelet count >600 on ≥ 2 at least ≥1 mo apart.

              2.  Exclusion of secondary causes of acute thrombocytosis.

              3.  ABSENSE of Philadelphia Chromosome


         
    • Workup:
      • Platelet count
      • R/O CML - Philedelphia chromosome (CML - can have isolated platelets, and basophilia can be in both).
      • JAK2 V617F - defines more aggressive course (50%).
        • Remainder of patients who are JAK2 negative have calreticulin mutation (no test avaialble yet!)
      • Low Glucose, high K+ (platelets metabolyze glucose release K)
      • Film: large platelets. 
    • Complications:
      • Less likely to progress to leukemia.
      • Arterial and venous thrombosis (1/3 of patients)
      • vWD Type II - if platelets > 1500 x10^6.
        • vWF binds to Glycoprotein, platelets can soak up.
    • Treatment:
      • Controversial (exact level of platlets to treat unknown)
        • Platelet count is not a good predictor for thrombosis (leukocytosis seems to be better predictor)
      • Latest recommendation 2012:  Treat with hydroxyurea + low dose ASA
        • Decreasing platelets decreases thrombosis risk and decreases secondary myelofibrosis
        • Indications for treatment:
          • Age > 60
          • Platelet Count > 1000
          • History of Thrombosis
      • Platelet lowering agents:
        • Use in patient with prior thrombotic event, risk factors for thrombosis and >65.
        • Drugs:
          • Hydroxyurea (Monitor leukocyte counts) + low-dose ASA.
            • Reduces arterial thrombosis and reduced risk of bleeding (regardless of plts count achieved)
          • P32 (radioactive phosphorus) alternative in older patients.
        • Splenomegaly: Ruxolitinib (COMFORT1 and COMFORT 2 studies)

    Acute Myeloid Leukemia - AML

    • Rapidly progressive malignancy characterized by failure of myeloid cells to differentiate beyond blast stage.
    • Mean age of dx is 67.
    • Risk factors:  DNA damage from prev chemo or rads. Myelodysplasia, myeloproliferative disorders, defects in DNA repair (fanconi anemia, Down's Syndrome), bone marrow failure (PNH, aplastic anemia).
    • Rapid progression!
    • Symptoms:
      • Cytopenias
        • Anemia: Fatigue, dyspnea
        • Thrombocytopenia: Easy bleeding
        • Low WBC: Fever
        • if WBC > 100,000, can get CNS/Respiratory Manifestations (confusion, headache etc..).
        • WBC can be low, normal or high.
          • Subtype: Aleukemic Leukemia (Marrow hypocellular)
          • Marrow full, but peripheral cells are low.
      • Can spread out of the marrow:
        • Gingival hypertrophy
        • Leukemia cutis. (violaceous plaques on skin)
        • Myeloid Sarcomas (skin, soft tissue bone).
        • Sweet Syndrome: Acute neutrophilic dermatosis. 
    • Labs:
      • CBC - anemia, thrombocytopenia, variable WBC
      • INR, aPTT, FDP, fibrinogen (if DIC)
      • Increased LDH, Increased uric acid, increased PO4 (released by leukemic blasts), decreased Ca2+
      • Baseline renal/liver function tests.
    • Diagnosis:
      • Diagnosis of AML≥20% of myeloblasts in blood or bone marrow. (Normal < 5%)
        • Blood Film:  **Circulating myeloblasts**
          • Auer Rods (Linear inclusion made of granuoles).
      • Flow cytometry: look at blast cells (distinguishes myeloblasts from lymphoblasts)
      • Cytogenetics to risk stratify.
    • Complications:
      • DIC (especially in acute promyelocytic leukemia)
      • Tumor Lysis Syndrome
        • Increase in: Uric Acid, Potassium, Phosphate  + Kidney Injury
        • Decrease in: Calcium (phosphate binding)
    • Classification:
      • See WHO classification.  Mostly based on cytogenetics (low vs. high risk).
      • 5-yr survival anywhere from 65% to 2%.
    • Treatment:
      • RAPIDLY FATAL!  Need treatment!
      • High risk of TLS --> use hydration, allopurinol, rasburicase (newer agent) with ALL PATIENTS!
      • If WBC >100,000 --> leukoreduction via machines, hydroxyurea, radiation.
      • Two stages:
        • 1. Induction (get into remission) called "7+3"
          • Chemo (Aka "7+3"):  Citeribine + Anthracycline
            • Citeribine (7 days)
              • [anti-metabolite, inhibits DNA synthesis]
            • Anthracycline (most commonly idarubicin) (3 days)
              • [intercalating DNA agent, leads to strand breaks]
          • Gets 80% into remission
        • 2. Consolidation
          • Keep in remission.
          • Younger or favourable risk disease:
            • Several courses of high-dose citeribine
          • Older or high-risk disease + HLA match
            • Allogeneic hematopoeitic stem cell transplant.
            • (high-dose citeribine not used in older patients d/t cerebellar toxicity)
        • If Palliative: low-dose citeribine and hydroxyurea.
    • Cure Rate:
      • 20-40% with standard chemo.
    • Must irradiate all transfusions (prevent GVHD) +/- EPO  +/- GCSF (if infection)

     

    Acute Promyelocytic Leukemia (APL)

    • One of many subtypes of AML.
    • Distinguished because it is one of the AML subtypes that has a different treatment.
      • 15:17 translocation --> fusion protein that puts retinoic acid receptor next to putative oncogene PML.
    • Treatment is the same, excent can use all-transretinoic acid (vitamin A derivative)
      • Binds to retinoic acid receptor in leukemic cells --> induces differentiation.
      • "All-trans retinoic acid induced differentiation syndrome" can occur.
        • Typically see WBC increase to extremely high levels (i.e. from 30,000 -> 130,000)
        • Also get capillary leaks: Dyspnea, peripheral edema, fever, hypotension, AKI, pleural/pericardial effusions (1-3rd week of treatment).
        • Treat with dexamethasonthe and temporary discontinuation of the drug!
        • Why WBC increases?
          • Typically a block in differentiation in the marrow (cells arrested in promyelocytic stage).  When you induce them to differentiate, they release into peripheral blood causing rapid increase in WBC count.
    • Other Differentiating Agents:
      • Arsenic Trioxide  (cardiac toxicity, QT prolongation).
    • 80% cure rates (~40% in other AMLs)

    Chronic Myeloid Leukemia - CML

    • Both myeloproliferative disorder and chronic leukemia.
    • Phases
      • Chronic (asymptomatic, fatigue, night sweats, weight loss, early satiety, splenomegaly)
      • Accelerated
      • Blast Phase
        • Manifests as AML (80%) or ALL (20% - lymphoblasts)
    • Pathophysiology:
      • Balanced translocation between chromosomes 9 and 22
      • Constitutavely active BCR-Abl tyrosine kinase - Philadelphia Chromosomes.
        • Phosphorylates secondary and tertiary messengers --> increases proliferation of WBCs. 
    • Presentation:
      • Asymptomatic (Accidental with elevated CBC)
        OR
      • Symptoms of fatigue, weight loss, night sweats, abdo discomfort, early satiety, bleeding (platelets)
      • Splenomegaly (most common exam finding)
    • Labs:
      • High WBC
      • Platelets (N or high), Hb (N or low)
      • High Uric Acid
      • High LDH.
      • As it gets worse --> more and more blasts.
      • Blood film:
        • Neutropilia and left shift granulopoeisis - Basophilia - common.
    • Diagnosis:
      • Diagnosis:

         

        • Cytogenetics - BCR-Abl 9:22. 
          OR
        • FISH - BCr-Abl 9:22
          OR
        • PCR: BCR-Abl fusion transcript

         

     

    • Treatment:
      • Diagnosis requires treatment even if asymptomatic.
      • Chronic Phase
        • *** Imatinib: BCR-Abl inhibitor ***
        • Unprecedented response rate (took survival from 20% to 90% at 5 years).
        • Nilotinib, Dasatinib.
          • Used if resistance to Imatinib.
          • Early studies (2013): highest response rates than imatinib.
      • Allogeneic Hematopoietic Stem Cell transplant
        • Only reserved for accelerated blast phase disease, or if resistant to BCR-Abl inhibitors.

     

    Chronic Myelomonocytic Leukemia (CMML)

    Myelofibrosis

    • Megakaryocytes produce fibroblast growth factor that stimulates collagen production and bone marrow fibrosis.
      • Impair marrow function and cause extramedullary hematopoiesis.
      • Considered a neoplastic process
    • Symptoms
      • Most patients symptomatic at diagnosis
      • Fatigue, night swets, weight loss, abdominal pain, early satiety from splenomegaly.
      • Extramedullary hematopoiesis:
        • Hepatosplenomegaly
        • Bone Pain: Vertebral column, etc..
      • Gout (Bone turnover)
      • Thrombosis: arterial/venous.
      • Pulmonary Hypertension: Unclear why. (platelet derived growth factors).
    • Labs:
      • Anemia
      • Elevated ALP, Uric Acid
      • Peripheral Smear:
        • "Leukoerythroblastic" picture
          • Left shifted granulopoiesis
          • Early white cells, nuclear RBCs (Erythroblasts)
          • Teardrop cells (means something in the marrow that doesn't belong there).
          • tearCell.jpg
      • Bone Marrow Bx
        • Difficult because of fibrosis
      • JAK2 Positive (50% of pts)
    • Causes:
      • Primary (Megakaryocyte proliferation)
      • Secondary:
        • Metastatic Cancer
        • Myelodysplasia
        • Myeloproliferative disorders (+ hairy cells)
    • Prognosis:
      • Age, symptoms, anemia, leukocytosis, number of blasts.
    • Treatment:
      • If asymptomatic: watchful waiting.
      • If symptomatic: palliative treatment (symptomatic, transfusions etc..)
      • Some therapies:
        • JAK2 inhibitors (Ruxolitinib) NEW!
          • Decreases spleen size slightly, improves constitutional sx (slightly), being researched!
        • Some respond to androgen therapy (danazol).  [Androgens drive hematopoiesis].
        • Hydroxyurea: helps hepatosplenomegaly, constitutional sx, thrombocytosis.
        • Splenectomy: high perioperative mortality.  Drops blood cell production. 
        • Splenomegaly: Ruxolitinib (COMFORT1 and COMFORT 2 studies)
        • Radiation: Sometimes used to avoid surgery, very limited response.
        • Stem Cell Transplant: Potentially Curative, but significant morbidity/mortality in older patients.

     

    Hypereosinophilic Syndrome (HES)

    • Syndrome:
      • Elevated Eosinophil count (>1.5 x10^9/L)
      • No Secondary cause
      • Evidence of Organ Involvement
    • Causes of secondary hypereosinophilic syndrome:
      • CHINA mnemonic
        • Connective tissue diseases
        • Helminthic infection
        • Idiopathic [HES]
        • Neoplasia
        • Allergy
    • Organ involvement:
      • Skin - Eczema/Erythroderma / Mouth sores
      • Lungs 
      • GI Tract - Abdominal Pain / tenderness
      • Heart - LV restriction + Increase echogenicity of myocardium
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