​Kembara Xtra - Medicine - Myeloproliferative Neoplasms

​Kembara Xtra - Medicine - Myeloproliferative Neoplasms
The pluripotent hematopoietic stem cell is the cell of origin for the myeloproliferative neoplasms (MPNs), a category of clonal diseases.
This article focuses on primary myelofibrosis (PMF), essential thrombocythemia (ET), polycythemia vera (PV), and chronic myelogenous leukemia (CML).
In addition to MPN unclassifiable, which is much more uncommon, the 2016 World Health Organization (WHO) MPN classification also includes chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia not otherwise specified (CEL-NOS), and mastocytosis.Unchecked myeloid precursor cell growth is a hallmark of CML.
Each MPN carries the risk of complications, such as thrombotic events, as well as transformation into acute leukemia or bone marrow fibrosis; PV is characterized by erythrocytosis, ET is characterized by thrombocytosis, and PMF is characterized by bone marrow fibrosis and extramedullary hematopoiesis. The natural history can last decades.


Epidemiology 

advancing years. The median age of diagnosis for MPNs is over 60.
CML: 1.6/100,000 per year; PV: 0.84/100,000 per year; ET: 1.03/100,000 per year; PMF: 0.47/100,000 per year

Pathophysiology and Etiology 

Genetic changes that activate hematopoiesis and cause the growth of myeloid, erythroid, and/or megakaryocyte lineage cells are the cause of MPNs.

Genetics

The oncogenic BCRABL1 fusion gene caused by a 9:22 translocation (the Philadelphia chromosome) defines CML. A constitutively active tyrosine kinase, the BCR-ABL1 fusion protein promotes cell proliferation, especially in granulocytes.
PV, ET, and PMF all have "driver" mutations that stimulate hematopoiesis, most frequently in the JAK2, MPL, and CALR genes.
More than 90% of BCR-ABL negative MPNs have a mutation in one of these three genes.
 Mutations in the Janus kinase 2 (JAK2) gene: JAK2 regulates hematopoiesis primarily through signaling through the erythropoietin (EPO), GMCSF, thrombopoietin, growth hormone, leptin, and IL-3 and IL-5 molecules. The JAK2 protein is constitutively activated by JAK2 mutations, which promote cell growth and increase survival time.
- 95% of PV, 55% of ET, and 65% of PMF cases had the JAK2 V617F mutation.
- 4% of PV cases have mutations in JAK2 exon 12
Mutations in the Myeloproliferative Leukemia Protein (MPL) gene: Mutations in the thrombopoietin receptor, which controls hematopoietic stem cells, particularly megakaryocytes, can result in excessive cell production.
- 3% of ET cases and 5% of PMF cases have MPL mutations.
Activated hematopoiesis, particularly of the megakaryocyte lineage, is caused by specific frameshift mutations in the calreticulin (CALR) gene, which encodes the calreticulin protein. The thrombopoietin receptor may be constitutively activated; this is an ongoing topic of research.
- 25% of cases of ET and PMF have CALR mutations.
As more driver mutations are discovered, they are divided into those that are "restricted," meaning that they only cause MPNs, and those that are "unrestricted," meaning that they may also be responsible for other myeloid neoplasms. Mutations that are deemed "restricted" include JAK2, MPL, and CALR.
likelihood FACTORS Any factor that enhances the likelihood of somatic mutations, such as exposure to ionizing radiation The majority of MPNs are caused by somatic mutations; familial examples have been reported. PV, ET, and PMF share mutations and can transition into one another.

Accompanying Conditions 
Major and small hemorrhagic events (acquired von Willebrand disease), thrombotic events (CVA, DVT, etc.), and Anemia, fibrosis of the bone marrow, osteosclerosis, and the development of acute leukemia from a blast
Hematopoiesis extramedullary

All MPNs may share the following symptoms. Constitutional signs are prevalent, while some people are asymptomatic. - Constitutional: weakness, exhaustion, fevers, night sweats, and weight loss
- Gastrointestinal: early satiety; belly fullness, discomfort, or pain - Musculoskeletal: discomfort in the bones
- Neurologic: headaches, lightheadedness, difficulty focusing, brief visual disturbances - Psychiatric: sleeplessness, impotence, and melancholy; more prevalent with some MPNs
- CML: gout and excessive sweating
- PV: facial plethora, gout, tinnitus, erythromelalgia, aquagenic pruritus - PMF: arthralgias, bone discomfort, early satiety, stomach fullness or pain, gastrointestinal hemorrhage - ET: unusual chest pain, erythromelalgia, livedo reticularis, transitory visual disturbance, fainting or syncope, and pregnancy loss ● The following physical findings may appear in all MPNs: - Splenomegaly, hepatomegaly, and pallor
 More frequent in some MPNs:
- Gouty tophi: CML
- PMV: facial plethora, gouty tophi, elevated blood pressure, and conjunctival injection Petechiae, livedo reticularis, and significant splenomegaly are all symptoms of the PMF, while petechiae, lymphadenopathy, and splenomegaly are symptoms of the ET.

Laboratory Results 

Initial examinations (lab, imaging)
CBC (complete blood count) with differential Metabolic panel (renal function, liver function, electrolytes), peripheral smear, and lactate dehydrogenase (LDH)
Follow-Up Tests for Uric Acid & Special Considerations
 BCR-ABL testing (1)[A]
BCR-ABL gene detection using reverse transcription polymerase chain reaction (RTPCR) and fluorescence in situ hybridization (FISH) to detect the 9;22 translocation/Philadelphia chromosome
Depending on the clinical situation, take into account: - EPO level, for diagnosing secondary causes of polycythemia; - testing for JAK2, MPL, and CALR gene mutations; - bone marrow biopsy (BMBx) and aspiration;
Studies on iron (ferritin, transferrin, and iron level)
- von Willebrand factor, for identifying acquired von Willebrand disease and determining whether there is a higher risk of bleeding BMBx and aspiration are frequently employed in diagnostic procedures/other to establish an MPN diagnosis.

Test interpretation The 2016 revision to the World Health Organization's categorization of acute leukemia and myeloid neoplasms (WHO) (1). - Although MPNs have many similarities, including the ability to convert into one another and the potential for expanded cell lineages, each one's prognosis and course of treatment differs greatly.
Leukocytosis, granulocytosis (neutrophil predominance), and immature and mature forms are all symptoms of CML. Metamyelocytes are frequently found in myelocytes.
- The diagnosis is made using the Philadelphia chromosome/BCR-ABL fusion gene.
- A blast crisis phase or an accelerated phase can develop in chronic CML.
 CML blast phase: WHO standards
20 percent or more explosions in the BM or PB, or
 PV—WHO criteria Infiltrative growth of blasts at an extramedullary location- All three of the major criteria must be met for a diagnosis, or the first two major criteria and the minor criterion. - Key requirements
 Men's hemoglobin >16.5 g/dL and women's hemoglobin >16.0 g/dL OR
>49%/48% Hematocrit OR
BMBx demonstrates hypercellularity for age, increased red cell mass (RCM), and trilineage growth with strong erythroid, granulocytic, and megakaryocytic proliferation and pleomorphic, mature megakaryocytes. JAK2V617F or JAK2 SH2 presence - Minor criteria
 ET—WHO criterion subnormal serum EPO level (1)[A]
- All four of the major criteria must be met for a diagnosis, or the first three major criteria and the minor criterion. - Key requirements
 Platelet count 450 109/L; BMBx showing proliferation primarily of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei; no discernible increase or left shift in neutrophil granulopoiesis or erythropoiesis; and only very rarely a minor (grade 1) increase in reticulin fibers.
 Failure to meet WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms.  JAK2, CALR, or MPL mutation present - Minor criterion:
 The presence or absence of a clonal marker for reactive thrombocytosis PMF - PMF has two stages: overt fibrotic stage and prefibrotic/early stage. Here are the criteria for the overt fibrotic stage.
- WHO criteria for overt PMF (1)[A]
All three major requirements, as well as at least one minor criterion, must be present for a diagnosis.
 Important criteria
Not matching WHO criteria for ET, PV, BCR-ABL1+ CML, MPNs, or other myeloid neoplasms; presence of megakaryocytic proliferation and atypia; accompanied by either reticulin and/or collagen fibrosis grades 2 and 3 Minor requirements include the presence of the mutations JAK2, CALR, or MPL or, in the absence of these mutations, the presence of another clonal marker or the absence of reactive myelofibrosis.
 At least one of the following, as determined by two separate determinations: Leukocytosis of at least 11 109/L, palpable splenomegaly, LDH beyond the upper limit of normal, and leukoerythroblastosis are all indicators of anemia that isn't caused by a coexisting illness.

Observation, phlebotomy/transfusion, medicines, and stem cell transplantation are all examples of management options.

General Actions 

PV: Phlebotomy is the first line of treatment for PV, and achieving goal hematocrit reduces mortality from cardiovascular or thrombotic events by four times in men and three times in women.
Transfusions for symptomatic thrombocytopenia and anemia
 Manage overall cardiovascular risk (treat hypertension, hyperlipidemia, diabetes, smoking, etc.) as MPN provides higher risk of thromboembolic events.

Medication 

CML: - Initial treatments include:
Tyrosine kinase inhibitors (TKIs) are used as the first line of treatment for patients in the chronic phase, accelerated phase, and blast phase who are being assessed for stem cell transplantation.
Imatinib is a first-generation TKI (1GTKI); nilotinib, dasatinib, and bosutinib are second-generation TKIs (2GTKI); and ponatinib is a third-generation TKI (3GTKI).
It is advised to use 1GTKI or 2GTKI throughout the low-risk chronic period.
2GTKI is favored in the chronic period of high risk.
While assessing for stem cell transplant, 2GTKI or 3GTKI are favored in the expedited phase.
TKIs may be given in the blast phase as patients wait for induction chemotherapy or a stem cell transplant.
- Supplemental treatments
An active field of research involves supplementing TKI therapy with pegylated interferon.
Aspirin (81 to 100 mg) is the first-line treatment for all patients with PV; it helps to prevent thrombotic consequences and treats microvascular events such ocular migraine, transient ischemic attacks, and erythromelalgia. High-risk PV patients who are elderly or have a history of thrombosis should undergo cytoreduction with pegylated interferon and hydroxyurea.
Consider hydroxyurea for low-risk patients who cannot tolerate phlebotomy for cytoreduction.
Consider using the JAK2 inhibitor ruxolitinib for high-risk patients who don't respond well to cytoreductive therapy.
First-line treatments for ET include aspirin (81 to 100 mg), which is recommended for patients with a history of thrombosis, a JAK2 mutation, microvascular problems, or vasomotor symptoms.
For high-risk ET patients (thrombosis, or age >60 years + JAK2 mutation), or for people with acquired von Willebrand syndrome, severe bleeding, or splenomegaly, cytoreduction in hydroxyurea is recommended. - Supplemental treatments
Consider pegylated interferon or anagrelide as an alternative to hydroxyurea when cytoreduction is necessary.
If aspirin is unable to relieve your symptoms, you may want to think about using hydroxyurea for cytoreduction.
PMF: - First-line treatments
If a transplant is not anticipated and platelets are below 50 109/L, ruxolitinib, a JAK2 inhibitor, may be used.
- Second-line drug treatment:
Low-risk patients who have troublesome symptoms may want to think about using pegylated interferon, hydroxyurea, or ruxolitinib.
Patients taking ruxolitinib who experience illness progression may be candidates for a more recent JAK2 inhibitor.
EPO 500 mUmL Erythropoiesis-stimulating drugs Patients with anemia who are not satisfactorily responsive to nutritional repletion and/or transfusion 
EPO > 500 mUmL: Take danazol, prednisone, lenalidomide, or thalidomide into consideration.

Referral 
For specialized advice, patients with MPNs or those suspected of having MPNs are referred to hematology/oncology.

Surgical Techniques 
Allogeneic stem cell transplant may be considered in high-risk PMF, CML's accelerated phase, and blast crisis.
In extreme situations, most frequently in PMF, splenectomy may be considered.

Continuous Care
​Patients with splenomegaly may be recommended to refrain from high-contact sports and other activities that raise the danger of rupture. Avoid settings that increase their risk of thrombosis, such as extended immobility.


Prognosis
The prognosis of CML is significantly correlated with the illness phase (chronic, accelerated, blast). The natural history of MPNs might extend decades.
- The median overall survival for patients in the blast phase is one year.
The outcome of TKI therapy is also highly linked with the prognosis for CML.
- Patients with BCR-ABL suppressed to less than 10% had a 97% overall survival rate after 3 months of treatment.
Patients with >10% BCR-ABL expression have an 87% chance of surviving overall.
● Despite having similar driver mutations, PV, ET, and PMF have very different prognoses: - PV: 14 years on average (24 years if under 60 years old) - ET: 20 years on average (33 years if under 60 years old) - PMF: 6-year median survival (or 15-years if under 60 years old).
The prognosis is also impacted by driver mutation; CALR typically imparts a better prognosis, but JAK2 or "triple-negative" status (no detectable JAK2, MPL, or CALR mutation) status normally confers a worse prognosis.
Poor prognosis is associated with transformation into acute leukemia, which happens more frequently in PMF and less frequently in ET.
- A poor prognosis is also associated with transformation into overt PMF with fibrotic marrow, which may happen more frequently in PV than ET.

---