Transcript Thrombocythemia - Oncology Hematology Associates

Thrombocythemia
Mark D. Browning, M.D.
February 22, 2017
Elevated Platelet Count
> 450,000
• Normal Platelet Count
– 150,000-450,000
• Causes of Elevated Platelet Count
– Reactive
– Tumors, Infection, Iron Deficiency
– Stress
– Splenectomy
– Vincristine
– Autoimmune Diseases, Other Myeloprolif. Dis
– *Essential Thrombocythemia..Jak2 Aby+/-
*Reactive Thrombocythemia
•
•
•
•
•
Iron deficiency
Chronic inflammatory disorders
Chronic infectious diseases
Malignancy
Other stem cell disorders such as
Polycythemia vera, Chronic myelocytic
leukemia, & idiopathic myelofibrosis
*Primary Thrombocythemia -Essential Thrombocythemia
• **>450,000 platelets/ul in the absence of
any other cause
• **Diagnosis of exclusion
• **Any cause of reactive thrombocytosis
must be considered
*Clinical History Thrombocythemia
• 79 yo male referred from family physician
for evaluation of elevated platelet count
• No complaints & USAF Retired
• He denies arthritis, infection, cancer, TIAs,
CVAs and family history of blood problems
• Platelet count increased from 250k, to
500k to 910k over the last 3 years
*Clinical
History…Thrombocythemia
Laboratory Information
(R/O Iron, Inflammation & Tumor)
•
•
•
•
•
Ferritin = 380 WNL
Erythropoietin = 5.9 WNL (4.2-28)
ESR = 1
Rheumatoid factor = 7.9
CT Abdomen/pelvis normal except for
diverticulosis
• JAK2 Mutation + V617F
Essential Thrombocythemia
Clinical Aspects
•
•
•
•
•
•
•
6,000 people in USA diagnosed/year
Life expectancy is not effected
F:M preponderance 2:1
Median age is 60
20% of patients <40
1/3 asymptomatic
2/3 vasomotor or thrombohemorrhagic
complications
*Myeloproliferative Disorders
Morphology
*Chromosome 9 …JAK2 Mutation
Myeloproliferative Class prior to
JAK2 Mutation Era
*Diagnosis of Essential
Thrombocythemia
Mutation Negative
*Diagnosis of Essential
Thrombocythemia+Mutation
*Essential Thrombocythemia
Vasomotor Symptoms
• Headache, light-headedness, syncope,
atypical chest pain, *acral parasthesia, visual
disturbances, livedo reticularis,
*erythromelalgia (burning pain of the hands
or feet associated with erythema and
warmth)
– events can be controlled with ASA
– some are resistant & need cytoreductive therapy
*Essential Thrombocythemia
Hypercoagulable
•
•
•
•
•
•
Venous & arterial thrombotic events
Distal vessel thromboses
Strokes
Coronary artery occlusions
Budd-Chiari syndrome or skin necrosis
Vasomotor symptoms: HA, dizziness,
parasthesias, & acrocyanosis
Primary Thrombocythemia
• Clonal disorder proven by G6PD
isoenzyme studies
• Overlaps with other MPD, 50% of patients
have leukocytosis &/or anemia
• Most detected on routine CBC
• Most are asymptomatic
• Very high platelet counts --bleed or
hypercoagulable
*Essential Thrombocythemia
Laboratory Studies
• CBC distinguishes CML, P.Vera &
Myelofibrosis
– WBCs & RBCs are not markedly elevated
– No teardrops or nucleated RBCs
• Normo/hypercellular marrow
– Megakaryocytes should be increased & No
Fibrosis
• Iron studies to exclude Iron deficiency
• ESR to exclude an inflammatory state
• JAK2 +/- & no 9/22 translocation
Increased # of Platelets
Increased Megakaryocytes
Essential Thrombocythemia
Thrombosis & Hemorrhage
• Major thrombosis 4 to 7%
• Studies vary
– Thrombosis 9-22%
– Hemorrhage 8-14%
Essential Thrombocythemia
Disease Transformation
• P. Vera - 2.7%
• Myelofibrosis - 4%
• Acute myeloid leukemia 1.4%
Essential Thrombocythemia
Management
• Indiscriminate use of harmful agents is not
warranted
• Make diagnosis accurately
• Evaluate for risk factors
• Treat patient according to each risk group
Essential Thrombocythemia
Risk Stratification
• Low Risk
– <60, No hx of thrombosis, Platelets <1.5M, no
cardiovascular risk factors (smoking,obesity)
• High Risk
– >60, Previous hx of thrombosis
• Intermediate Risk
– neither high nor low risk
Essential Thrombocythemia
Management
• Low-Risk
– incidence of thrombosis is 1.9/100 patient
years & not much different than the 1.5/100
patient years for age matched controls
– No intervention
Essential Thrombocythemia
Management
• Intermediate-Risk Patients
• Low-dose ASA
Essential Thrombocythemia
High-Risk
• Study with median f/u of 27 months
• 3.6% risk of thrombosis if platelets
<400,000
• 24% risk of thrombosis of platelets
>400,000 and not controlled
• Supports cytoreductive therapy
• Hydroxyurea, Anagrelide, Interferon, P-32
Myelofibrosis
Mark D. Browning, M.D
Oncology/Hematology Associates
February 22, 2017
Myelofibrosis
• Can present de novo
• Can be a secondary manifestation of:
– CML
– Polycythemia vera
– Essential Thrombocythemia
• G6PD isoenzymes & cytogenetics show it
is a clonal malignancy involving all
hematopoietic cell lineages
*Myelofibrosis
• *Marrow fibrosis is its most distinguishing
feature
• The malignant chain is a malignant stem
cell line, especially megakaryocytes
• Its most distinguishing feature is:
– Fibrosis
– Fibroblasts & reticuloendothelial cells are
reacting to the malignant stem cell line
Myeloproliferative Disorders
Morphology
• CML – uncontrolled myeloid line
– Ph chr +
• P. Vera –uncontrolled RBC line
• Essential thrombocythemia – uncontrolled
megakaryocyte line
• Myelofibrosis --- excess fibrous tissue in
marrow
Myelofibrosis
Clinical Manifestation
• Non-specific symptoms & signs
– Fatigue
– Malaise
– Abdominal distention & abdominal pain
– *Marked splenomegaly results from
extramedullary hematopoiesis
– Dragging sensation in the abdomen, LUQ
pain & early satiety
Myelofibrosis
Clinical Manifestaions
• Less prone to splenic infarction than
patients with CML
• Patients with rapidly progressive, acute
myelofibrosis, can complain of bone pain
& tenderness, especially over the sternum
Myelofibrosis
Laboratory Studies
• CBC distinguishes Myelofibrosis from CML
• Normochromic, normocytic anemia with
prominent anisocytosis & poikilocytosis
• **NUCLEATED RED BLOOD CELLS &
TEARDROPS in peripheral smear
– Characteristic suggesting extramedullary
hematopoiesis in the spleen
• Giant platelets & dysplastic leukocytes (PelgerHuet anomaly)
*Nucleated Red Blood Cells
*Teardrop RBC
Myelofibrosis
Laboratory Studies
• Moderate increased WBC (not like CML)
• Disease progression, WBCs fall to subnormal
levels secondary to poor production or increased
destruction by the spleen
• Platelets may be any number at presentation
– Falls to low levels or can increase dramatically after
treatment
• Thrombocytosis after splenectomy
Myelofibrosis
Laboratory Studies
Diagnosis
• **Definitive diagnosis depends on
fibrosis in the marrow biopsy
• **Marrow is difficult or impossible to
aspirate & core biopsy is required
• **Biopsy can show variable distortions
of marrow structure ranging from
complete fibrous replacement to patchy
losses of hematopoietic and fat cells
*Marrow Fibrosis
*Myelofibrosis
Diagnosis
• Immature & abnormal megakaryocytes are
frequent
• *Increases in reticulin & collagen can vary
depending on the severity & progression
of the disease process
Myelofibrosis
• Can develop as a secondary
manifestation of CML, Polycythemia
vera & Essential Thrombocythemia
• Proliferating megakaryocytes is a
prominent component
– Suggests key role of Megakaryocyte &
platelet growth factor in stimulating the
fibrosis
• Need to inspect the marrow for nests of
malignant cells
Myelofibrosis
Differential Diagnosis
• T & B cell lymphomas
• Hairy-cell leukemia
• Miliary tuberculosis
• CML
*Myelofibrosis
Laboratory Studies
• Chromosomal abnormalities are
frequent…only predominant
karyotype…JAK2 mutation noted in 2005
• Other labs follow other Myeloproliferative
Disorders:
– Increased Uric acid & LDH
Myelofibrosis
Disease Course
• Protracted course
• Median survival is 5 to 8 years
• Is a disorder of older patients, death may
be from natural causes
-1/3 or less will die of complications resulting
from their hematopoietic disorder
-Unlike CML, <10% progress to acute
leukemia
*Myelofibrosis Risk Factors(7)
•
•
•
•
•
•
•
> 60 years of age
Hepatomegaly
Weight loss
Anemia (Hgb <10)
Leukocytosis (WBC > 30,000)
Leukopenia (WBC < 4,000)
Thrombocytopenia (<150,000)
• Survival < 3 years if > 2 risk factors
• Survival 8-10 years if < 2 risk factors
Myelofibrosis Therapy
• Ruxolitinab…monoclonal approved 2011
– Weekly Rx & Improvement in splenomegaly
– Anti-Jak2Aby
• Allogenic stem cell transplant
– 5 year survival rate of 47%
• Androgen therapy
– Improves anemia in 25% of patients
– Need monitoring of LFTs & prostate screening
• Hydroxyurea…decreases spleen size,
controls platlet & WBC counts
Myelofibrosis Therapy