​Kembara Xtra - Medicine - Acute Myeloid Leukemia

​Kembara Xtra - Medicine - Acute Myeloid Leukemia 
Acute myeloid leukemia (AML) is defined by the growth of aberrant, immature myeloid progenitors (blasts), which are less able to specialize and cause bone marrow failure as well as a number of systemic symptoms.
Historically, the French-American-British (FAB) classification system separated AML into subtypes (M0 to M7) based on the cell shape.
The World Health Organization's (WHO) classification makes an effort to offer more insightful prognostic data.
- AML with the chromosome 16 inversion inv(16), translocation t(8;21), and t(15;17) genetic abnormalities.
- AML with multilineage dysplasia: the existence of an earlier MPN or myelodysplastic syndrome (MDS) that developed into an AML
- AML and MDS-related therapies
- AML, not elsewhere classified
- Biphenotypic acute leukemias, or acute leukemias of uncertain lineage

Epidemiology 19,940 cases are anticipated in 2020, making it the most prevalent type of adult leukemia Male predominance Female predominance
Incidence
The median age is 67 years, and the incidence of AML rises with age.


Pathophysiology and Etiology 

Unknown exact causes, but there are several risk factors that have been found (see "Risk Factors").
 Three risk groups Genetics
Good risks include inv(16), t(8;21), and t(15;17).
- Normal risk: Monosomy 5 and 7 (usually secondary AML), deletion 5q, anomalies of 11q23, or complex karyotype are at low risk if your karyotype is normal.
Internal tandem duplications of the FLT3 gene (FLT3-ITD), in particular, have been linked to poor prognosis in AML. These and a growing list of (onco)gene mutations, including as NPM1, IDH1/2, DNMT3A, and P53, have been investigated to further categorize patients according to risk.

Risk factors include Down syndrome, Fanconi anemia (52%), neurofibromatosis, Li-Fraumeni syndrome, Wiskott-Aldrich syndrome, Kostmann syndrome, and genetic predisposition (such as Down syndrome).
Immunodeficiency conditions with radiation exposure
 MDS Exposure to chemicals and drugs (nitrogen mustard, alkylating agents, and benzene) 

Prevention 
None known at this time, however high-risk MDS treatment with hypomethylating drugs (5-azacitidine [Vidaza]) has been proven to delay the transition from MDS to AML.

Accompanying Conditions 

Leukostasis (high blast quantity and higher blast adhesive ability) Disseminated intravascular coagulopathy (DIC), which is more common in acute promyelocytic leukemia (APL) but can occur in any type of AML
Tumor lysis syndrome (TLS): naturally occurring or brought on by chemotherapy

History 

fatigue (caused by anemia or a tumor burden), bleeding (caused by low platelets or DIC), and trouble getting rid of infections (caused by neutropenia or immunological dysregulation).


clinical assessment 
Lymphadenopathy (typically reactive) - Fever, hemorrhage, pallor, splenomegaly, and hepatosplenomegaly - Mostly nonspecific and connected to marrow or tissue infiltration
Occasionally, individuals will appear with evident extramedullary sites of leukemia (such as skin infiltration or finally a myeloid sarcoma), especially if the central nervous system (CNS) is affected.

Differential Diagnosis: Virus-induced lymphadenopathy, organomegaly, and cytopenia
Immune cytopenias, such as SLE (systemic lupus erythematosus),
Other marrow failure and infiltrative disorders, such as aplastic anemia, paroxysmal nocturnal hemoglobinuria, MDS, and Gaucher disease, as well as drug-induced cytopenias

Laboratory Results 
The CBC reveals low levels of platelets, neutrophils, and RBCs.
 Cytogenetics, flow cytometry, and histology of the bone marrow to determine the diagnosis and prognosis
● ESR
 Lactate dehydrogenase (LDH) and uric acid levels may increase (for instance, in TLS).
 A prolonged coagulation profile, such as DIC, can be normal.
Drugs that could affect lab findings include corticosteroids and chemotherapeutic drugs.
 Additional unique tests: A spinal tap might show fluid containing leukemic cells.
Organomegaly may be found through an abdominal CT scan or ultrasonography.
Other/Diagnostic Procedures
In most cases, bone marrow tests are required to make the diagnosis.
Aspirates: to examine cell shape, cytochemistry, and immunophenotyping (which can determine the AML's stage of development); cytogenetics: to look for chromosomal abnormalitiesBiopsies offer important details about cellularity, architecture, and other factors.
Interpretation of Tests
 The natural architecture of the marrow is typically effaced, and the leukemic blast count is 20% or higher.
Leukemic cells may be present in the spleen and liver.


Management 

The mainstay of AML therapy has traditionally been traditional (cytotoxic) chemotherapy, which consists of the induction and consolidation phases of maintenance (APL), but more recently, hypomethylating agents such azacitidine have been used to treat other transplant-ineligible AML patients.
 High-risk AML treated with bone marrow transplantation (BMT)
Induction chemotherapy for AML has seen only minor advancements. Supportive care had much improved.
UNSPECIFED MEASURES
 Thorough evaluation of renal, coagulation, liver, heart, and bone marrow parameters (risk for DIC)
 Complementary therapy with
- Proper hydration - Packet RBC and platelet transfusions tailored to the patient's needs (platelet threshold as low as 5,000); usage of leukoreduced, irradiated blood products because all patients are eligible for BMT.
- Stay away from antiplatelet medications (like aspirin products).
- When a neutropenic patient develops a fever (even a low-grade fever), follow the guidelines for febrile neutropenic patients.
Aspects of Geriatrics
The treatment of older individuals (60 to 65 years old) continues to be difficult. These individuals are given so-called nonmyeloablative or reduced-intensity BMT.
Granulocyte colony-stimulating factor [G-CSF] addition may lessen toxicity in elderly patients (but it is not widely acknowledged).
 In older persons who are ineligible for conventional chemotherapy, hypomethylating agents like 5-azacitidine or decitabine, either with or without Venetoclax, have found widespread adoption and have been shown to prolong survival.
pregnant women's issues
In the second and third trimesters, chemotherapy is a possible choice.
First Line: MEDICATION
AML with t[15;17] (APL, AML)
- Both arsenic trioxide and all-trans retinoic acid (ATRA) encourage granulocyte development. They can be used together to treat low- and intermediate-risk APL without the need of chemotherapy.
- In the high-risk group, idarubicin is frequently added to induction therapy.
- Monoclonal anti-CD33 (Myelotarg) is further being added to reduce the amount of chemotherapy needed to treat this curable leukemia.
 AML treatment for young adults: AML (in contrast to APL)
- Induction (anthracycline and cytarabine with daunorubicin or idarubicin): The commonly used combination is 3 + 7 (anthracycline is administered for 3 days and cytarabine for 7 days), however more intense regimens using high-dose cytarabine (HiDAC) or high doses of anthracycline are also possible.
- For AML with MDS alterations or therapy-related AML, a liposomal formulation of daunorubicin and cytarabine (Vyxeos) is now available.
In younger individuals, remission is often strengthened by the following:
- Three to four cycles of HiDAC and BMT are saved for recurrence time in good-risk AML.
- Allogeneic BMT is followed by one to two cycles of HiDAC (until a donor is found) in patients at minimal risk.
- Intermediate-risk AML should be managed according to the characteristics of each patient, the accessibility of donors, and the availability of clinical trials. Even individuals with intermediate risk can benefit from allogeneic BMT, according to a meta-analysis.
AML treatment for elderly persons (>65 years of age) is very difficult. These patients have a low performance status, are more likely to have secondary AML, have more comorbid conditions, have shorter remissions, and have poorer overall survival rates. For secondary and therapy-related AML, a drug called liposomal daunorubicin and cytarabine has received approval.
– For patients with good performance status, intensive chemotherapy may be feasible; alternate regimens including mitoxantrone, fludarabine, and clofarabine
- The following innovative (targeted) agent choices are available to newly diagnosed patients who are 75 years of age or older or who have problems that prevent them from undergoing severe induction therapy.
Low-dose cytarabine combined with glasdegib (DAURISMO, Pfizer Laboratories)
 Hypomethylating drugs (decitabine [Dacogen] and azacitidine [Vidaza]) combined with the IDH1 inhibitor ivosidenib (Tibsovo)
Venclexta, a BCL-2 inhibitor, and hypomethylating drugs (azacitidine [Vidaza], decitabine [Dacogen])
In addition to induction and consolidation chemotherapy, FLT-3 inhibitors such midostaurin (Rydapt) and gilteritinib (Xospata) are approved for the treatment of AML that has relapsed or become resistant to treatment.
For relapsed/refractory AML, the drugs ivosidenib (Tibsovo; an IDH1 inhibitor) and enasidenib (Idhifa; an IDH2 inhibitor) have received approval. Similar to the differentiation syndrome found in ATRA or arsenic-treated APL patients, both of these drugs have the potential to cause it.
Comorbidities are a contraindication; therapy needs to be customized.
Precautions - If organ failure occurs, some medications may need to be avoided or their dosage lowered (for example, anthracyclines shouldn't be used in individuals who already have cardiac issues).
– During treatment, patients will experience immunosuppression.
Don't use live vaccinations. As soon as the patient is exposed, give them an immunoglobulin for measles or varicella-zoster.
Important potential interactions The toxicity of 6-mercaptopurine is increased by allopurinol.
● Midostaurin is a targeted therapy for AML with FLT3 mutations (both ITD and TKD). For relapsed/refractory AML with corresponding IDH mutations, Ivosidenib (IDH1 inhibitor) and Enasidenib (IDH2 inhibitor); for relapsed/refractory AML with CD33 expression, Gemtuzumab ozogamicin (anti-CD33 monoclonal antibody).
Next Line
Usually, allogeneic BMT and reinduction chemotherapy are offered to healthy, younger patients.
Older individuals might receive a targeted drug (FLT3 or IDH 1/2 inhibitor) along with or without venetoclax.

Problems to Refer 
Because finding a donor may be necessary, send the patient to a transplant clinic as soon as possible.

Surgical Techniques 

BMT: The patient's performance status, comorbidities, and AML risk factors should be taken into account while deciding between a myeloablative and nonmyeloablative treatment. In individuals with intermediate- or high-risk AML or in second remission in all other AML patients, allogeneic BMT is typically indicated. In the past, matched related donors were favoured over matched unrelated donors (reduced chance of graft versus host disease); however, more recent data indicate equal outcomes as a result of substantial advancements in allogeneic transplant protocols and posttransplant care.
 Autologous BMT may be appropriate in specific circumstances (e.g., no donor is available); Haploidentical transplants and cord blood have emerged as alternate sources of hematopoietic stem cells for adults that exhibit comparable outcomes as well.

AML treatment for admission needs inpatient care, typically on a dedicated unit. Admission and IV antibiotics are often needed for febrile neutropenia episodes.
In the event of extravasation, IV may result in chemical burns if proper hydration is not taken to prevent TLS.

Patient Follow-Up Monitoring
 Additional bone marrow tests to confirm remission and to rule out relapse.
Follow CBC with differential, coagulation studies, uric acid level, and other TLS-related chemistries (creatinine, potassium, phosphate, calcium); check urine function at least once per day during the induction period, then less frequently as needed thereafter.
Weight and blood pressure checks should be performed often while receiving therapy.

For severe mucositis, a total parenteral nutrition (TPN) diet


The prognosis AML remission rate is 60–80%, whereas the long-term survival rate is just 20–40%. Age, cytogenetics, and genetics are the prognostic groups that account for the vast range of prognosis.

Complications include febrile neutropenia and other acute chemotherapeutic side effects, TLS, and DIC.
 Late-onset cardiomyopathy in anthracycline-treated patients Chronic chemotherapy adverse effects (secondary malignancies) Graft versus host illness in allogeneic BMT recipients

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