​Kembara Xtra - Medicine - Myelodysplastic Syndrome

​Kembara Xtra - Medicine - Myelodysplastic Syndrome 
The heterogeneous category of clonal stem cell illnesses known as myelodysplastic syndromes (MDS) is defined by peripheral blood cytopenias such as anemia, thrombocytopenia, and/or neutropenia.
An aberration of development or differentiation in particular cell lines is referred to as dysplasia. These alterations in the bone marrow that occur in MDS give rise to a propensity for acute myelogenous leukemia (AML) transformation.

Prevention Incidence
Incidence rates in the US range from 3 to 4 cases per 100,000 people per year, rising to 35 cases per 100,000 people per year for patients over 60.
The prevalence of MDS in the country was over 60,000, and it is continuing to rise as the population ages.


Pathophysiology and Etiology 
Mutations in hematopoietic blood cell lines are the cause of MDS.
Peripheral cytopenias, caused by inefficient marrow hematopoiesis (premature cell death), are the clinical hallmark of MDS.
Nongenetic mechanisms include apoptosis, pyroptosis, deregulated immunity, and inflammatory cytokine amplification. Low-risk MDS (LR-MDS) are characterized by deregulated immunity and apoptosis, whereas high-risk MDS (HR-MDS) are characterized by clonal expansion and transformation to AML. Apoptosis, pyroptosis, and maybe autophagy are three separate methods by which stem cells in LR-MDS undergo programmed death.
- Apoptosis: In LR-MDS, proapoptotic cytokines (TNF- and IL-6) and tumor necrosis factor- (TNF-), TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand, play a significant role in stem cell apoptosis.
- Pyroptosis: This is an alternative form of apoptosis that results in inflammation in the cells.
A pore is formed in the plasma membrane of the cells as a result of the activation of nod-like receptors, which also causes the creation of the inflammasome complex, water ingress, cell swelling, and cell death. This may also explain the macrocytosis and swollen cells that are characteristic of MDS.
Upregulation of NF-B and increased activity of the Bcl2 and inhibitors of apoptosis protein (IAP) families have both been linked to the evolution of AML. This is assumed to be a strategy for getting around the bone marrow microenvironment's apoptotic phenomena.

Genetics: More than 90% of MDS patients have recurrent somatic mutations.
 Gene mutations can result in:
- TET2, EZH2, IDH1, IDH2, DNMT3A, and ASXL1 are involved in epigenetic regulation.
- TP53: DNA repair
- Regulators of transcription: BCOR, ETV6, RUNX1.
- RNA splicing: ZRSR2, SF3B1, SRSF2, U2AF35
- STAG2 cohesin complex
- Signaling: JAK2, CBL, and NRAS
 Changes to the epigenetic moderators: The idea is that any mutations that result in a gain of function in the DNA methyltransferases (DNMT3A and DNMT3B) cause hypermethylation, which is a mechanism for gene silence that aids in clonal evolution.
It is unclear how the identical phenotypic appearance of myelodysplasia and cytopenias is caused by these various molecular and genetic processes.

Age, tobacco use, chronic exposure to chemicals like benzene, pesticides, and insecticides, prior radiation or chemotherapy, inherited disorders like Fanconi anemia, Shwachman-Diamond syndromes, severe congenital neutropenia, and familial platelet disorder, and end-stage renal disease have all been linked to an increased risk in patients over the age of 60.


Prevention 

MDS risk may be reduced by avoiding industrial substances known to cause cancer, such as benzene, as well as tobacco.

Accompanying Conditions 

Hematologic problems including paroxysmal nocturnal hemoglobinuria and myeloproliferative disorders

History The kind and severity of cytopenias determine the clinical course of MDS patients.
Common symptoms include recurrent infections, bleeding problems, exhaustion, weight loss, and exertional dyspnea.
Fevers, night sweats, and weight loss are rare, and the most prevalent symptom of anemia is fatigue, which is frequently out of proportion to anemia.
Assess your exposure to toxins, such as alcohol or past chemotherapy.


clinical assessment 
Generalized pallor and ecchymosis due to anemia and thrombocytopenia, respectively; a rare occurrence of hepatosplenomegaly as a result of extramedullary hemopoiesis, particularly in MDS/MPN overlapping syndromes; and a rarity of lymphadenopathies.


Acute leukemia differential diagnosis: AML
Hypoproliferative anemia can be caused by vitamin B12 and folate deficiency.
idiopathic cytopenia of unknown significance, idiopathic dysplasia of unknown significance, clonal hematopoiesis of indeterminate potential (CHIP), and clonal cytopenia of unknown significance are indolent myeloid hematopoietic disorders that do not meet diagnostic criteria for MDS. Other risk factors include HIV, chronic liver disease, excessive alcohol consumption, and infections of the bone marrow such as HIV, tubercul


Laboratory Results 

Initial examinations (lab, imaging)
It is recommended to assess a patient's complete blood count, peripheral smear, chemistry, viral investigations (HIV and hepatitis panel), and vitamin levels (B12 and folate).
The following minimal diagnostic prerequisites were established by the International Working Group (IWG):
- The exclusion of any other possible causes of the dysplasia or cytopenia, stable cytopenia for less than six months or for two months with karyotype or bilineage dysplasia.
 The MDS diagnosis entails:
- Dysplasia (less than 10% in one of the three main bone marrow lineages)
- 5–19% blast cell count
- Chromosomal anomalies that are in line with MDS diagnostic techniques or other
— Histopathology. To differentiate MDS from AML and to carry out karyotype tests, fluorescence in situ hybridization (FISH), and mutational studies, a bone marrow examination is necessary.
- Blast%: 20% is indicative of AML; 20% is consistent with MDS.
— Cytogenetics. 30-80% of MDS patients have clonal chromosomal abnormalities. Submicroscopic changes (microdeletions, point mutations) offer diagnostic support in the remaining individuals (20–70%).
When in doubt, study of somatic mutations and bone marrow flow cytometry can provide proof of clonal illness.
Interpretation of Tests
Macrocytic anemia with potential basophilic stippling, hyposegmented neutrophils (pseudo Pelger-Huet), and thrombocytopenia are among the hematologic abnormalities on the blood smear.
Low reticulocyte indexes indicate a condition that is hypoproliferative.


Management 
Early treatment for LR-MDS patients who exhibit signs of anemia, neutropenia, and/or thrombocytopenia does not increase long-term survival.
- The initial course of treatment is based on the particular cytopenia.
Allogeneic stem cell transplant (SCT) is the sole curative option for higher risk patients, hence a precise prognosis evaluation is essential for therapeutic decision-making. Multiple scoring systems have been devised to achieve this goal:
- Six distinct conditions are listed in the World Health Organization (WHO) guidelines: MDS with single lineage dysplasia, MDS with ring sideroblasts, MDS with excess blasts, MDS with multilineage dysplasia, MDS with isolated del(5q), and MDS unclassifiable.
- Based on the quantity of cytopenias, karyotype, and blast proportion in the bone marrow, the International Prognostic Scoring System (IPSS) score divides patients into four groups (low, intermediate 1, intermediate 2, and high). In addition to the IPSS, the MDAS (Global MD Anderson) score improves prognostic accuracy.


First Line of Medicine
Blood transfusions and erythropoiesis-stimulating agents (ESA) for MDS-related anemia
Lenalidomide is used to treat anemia in MDS with isolated del(5q) (5); it reduces the need for transfusions and can cause a median increase in hemoglobin of 5.4 g/dL. ESA have a 30-60% response rate in LR-MDS; indications: hemoglobin 10 g/dL and erythropoietin level 500; uncommon complications: worsening hypertension and thromboe
Thrombopoietin receptor agonists (romiplostim, eltrombopag) may be used in certain circumstances to treat MDS-related thrombocytopenia and neutropenia (with cautious monitoring due to its potential for leukemic transformation). If clinically necessary, G-CSF and antibiotics can be used to treat neutropenia.
Low-intensity chemotherapy - The U.S. Food and Drug Administration has given the go-ahead for the use of hypomethylating agents (HMA) in LR-MDS patients who failed to respond to the first line of treatment.
HMA are medications that treat illnesses. Azacitidine and decitabine are two examples.
HMA bind to DNMT1, which results in DNA hypomethylation.
Additional clinical trials are required for alemtuzumab. Immune treatment. High-intensity chemotherapy. Induction chemotherapy combined with allogenic SCT can sustain remission in 30–50% of patients.
SCT - Allogenic SCT is still the only curative option, but due to its toxicity, it should only be used in individuals with high-risk diseases who are stable enough to endure treatment.
Patients under the age of 70 who have a suitable donor and concomitant conditions should be taken into account.
 Relapse or complications connected to the transplant are to blame for mortality following the procedure.
Next Line
Depending on the patient's severity (low vs. high risk), cytopenias, and likelihood of transplantation, clinical trials may be an option.


Referral 
A hematologist-oncologist should assess patients with chronic cytopenias of unclear origin.
It is advised to have a hematopathologist examine the bone marrow.
 A bone marrow transplant group referral for SCT evaluation

Further Therapies
Controlling iron excess. In patients who depend on blood transfusions, iron chelation is frequently considered.
 Potential agents. There are currently ongoing clinical trials for immunological therapies using CD52 monoclonal antibody antagonist.

Surgical Techniques Allogenic SCT, as previously mentioned

Admission 
A hospital hospitalization is required for complications such bleeding, neutropenic fever, and having SCT.

Patient Follow-Up Monitoring
Regular complete blood counts are used to monitor MDS and determine whether transfusions are necessary. If an infection develops, severe neutropenia may call for the use of antibiotics.
Bone marrow testing is typically prompted by cytopenias getting worse.

Diet 
Alcohol consumption, meat, vegetable, and fruit consumption don't seem to have a big impact on the likelihood of getting sick.


Patient education should include information on signs that should urge the patient to start receiving blood transfusions or antibiotics, as well as regular follow-up and medication compliance.

Prognosis 
Overall, the prognosis for MDS patients varies, with median survival varying based on MDS categorization from 6 months to >5 years.

Complications 
Rather than AML conversion, infection and bleeding are the main causes of death.
 Chronic anemia or iron overload-related increased risk of cardiovascular disease
 Iron excess may lead to hepatic impairment.