AML | Medhub

AML

Pathophysiology

In most cases, AML arises as a de novo malignancy.1 Its’ pathogenesis entails the appearance of a clonal population of myeloid cells, the proliferation and differentiation of which have been altered due to genetic and molecular changes, including: 1

• Large chromosomal rearrangements, such as t(8:21)
• Mutations in signaling molecules and enzymes, such as FLT3, STAT3, and DNMT3A

As a result, the maturation of myeloid precursor cells is disrupted, leading to the development of abnormal white and red blood cells and platelets and a corresponding decrease in their healthy counterparts.7

 

Causes

Although the cause of most cases of AML is unknown, there are several risk factors:2

• Smoking
• Male gender and older age
• Overexposure to organic solvents, such as benzene
• Treatment for another cancer—particularly chemotherapy and radiation therapy
• Affliction with a chronic blood disease, such as polycythemia vera, essential thrombocythemia, and myelodysplastic syndrome

 

Epidemiology
 Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with an incidence of over 20 000 cases per year in the United States alone1. The overall prevalence in Sweden was 13.7 per 100,000 persons in 2014.4 Roughly 1.4 times as many males are affected versus females,3 and the incidence of AML is 10-fold higher in persons aged 65 years and over compared with individuals aged under 65 years.3 The 5-year survival rate for AML patients is approximately 27%.3

 

Symptoms

AML patients typically experience anemia and moderate and nonspecific, flu-like symptoms. Common symptoms include:7

• Fever.
• Shortness of breath.
• Easy bruising or bleeding.
• Petechiae (flat, pinpoint spots under the skin caused by bleeding).
• Weakness or feeling tired.
• Weight loss or loss of appetite.

 

Diagnosis

In addition to routine physical examination and complete blood count, the following tests are performed to diagnose AML6:
 

Cytogenetic analysis- A mandatory element of the diagnostic workup to detect chromosomal abnormalities. Per the WHO, “AML with recurrent genetic abnormalities” comprises eight balanced translocations and inversions (and their variants); “AML with myelodysplasia-related features” is diagnosed, based on nine balanced rearrangements and several unbalanced abnormalities, when the blood or marrow blast count is ≥ 20%. 6

Morphology- On blood,≥ 200 leukocytes, and on marrow smears,  ≥ 500 nucleated cells should be counted. AML is defined by a blast or marrow count ≥ 20% (except for AML with t(15;17), t(8;21), inv(16), or t(16;16)). 6

Immunophenotyping- Generally, in the disease, ≥ 20% of leukemic cells express markers of AML—typically, early hematopoiesis-associated antigens but not markers of myeloid and monocytic maturation. 6

Screening for genetic mutations- Patients should be tested for mutations in 6:

• NPM1, CEPBA, and RUNX1, which define disease categories
• FLT3 activating mutations (both ITD & TKD) of which have prognostic value and can be targeted by tyrosine kinase inhibitors  [<hyperlink to article 1A - FLT3 Diagnosis>
• TP53 and ASXL1, which are associated with a poor prognosis

 

Treatment (Curative intention with high dose chemotherapy) 9

The general approach to current therapy has not changed substantially in recent years. The initial assessment evaluates whether a patient is considered a candidate for intensive induction chemotherapy. Although an assessment of the risk of treatment-related mortality (TRM) after intensive therapy is usually most relevant in older patients (commonly above the age of 65 years), age is merely one, and not the most important, predictor of TRM. Therefore, age alone should not be the decisive determinant in guiding therapy. 6

Results from cytogenetics should be obtained preferably within 5 to 7 days. Results from NPM1 and FLT3 mutational screening should be available within 48 to 72 hours (at least in patients who are eligible for intensive chemotherapy), and the results from additional molecular genetic testing should be available within the first treatment cycle. 6

 

Induction Therapy
Eligible patients first undergo induction chemotherapy to achieve complete remission (CR). Unfortunately, minimal residual disease often persists in CR, and  relapse will inevitably occur if treatment is discontinued. Therefore, a favorable response to induction therapy should be followed by consolidation therapy in order to eradicate any residual disease and achieve lasting remission.

Induction therapy consists of 3 days of an anthracycline and 7 days of cytarabine. Complete remission rates are achieved of 60% to 80% in younger adults and 40% to 60% in those aged ≥ 60 years. 6

 

Consolidation Therapy
Patients in remission should be offered consolidation therapy to eradicate residual disease and prevent relapse. Available options for consolidation include chemotherapy and allogeneic hematopoietic stem cell transplant (allo-HSCT). When choosing between these different options, the risk of TRM should be weighted against the risk of treatment failure or relapse. 1
Consolidation regimens include single-agent cytarabine at high doses and multiagent chemotherapy which lead to similar outcomes. 6
Open questions remain regarding the optimal number of cycles of consolidation therapy. In most studies 2-4 cycles have been given after attainment of CR.6
 

Allogeneic HCT
AML is the most frequent indication for allogeneic HCT, with a 10% annual increase in transplants performed worldwide. Expanded use of mismatched and unrelated donors and cord blood means that a donor can be found for most patients. Further, nonmyeloablative or reduced-intensity conditioning (RIC) regimens allow allogeneic HCT for patients aged up to 75 years. Nonetheless, in reality, only a minority of AML patients undergo transplantation due to older age, comorbidities, toxicity of prior therapy, inability to achieve remission, and early relapse or refractory leukemia. 6
 

Patients unfit for intensive chemotherapy

Some AML patients will not tolerate intensive chemotherapy. Several risk scoring systems are available that use patient-specific and disease specific factors to make the choice of intensive or alternative treatment. 6

Treatment alternatives for unfit patients are limited to best supportive care, low-intensity treatment, or clinical trials with investigational drugs. 6

 
References
1. De Kouchkovsky I, Abdul-Hay M. Blood Cancer J. 2016 Jul;6(7):e441.
2. American Cancer Society. Acute myeloid leukemia [Internet]. [cited 2019 Feb 21] Available from: https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq.
3. Surveillance Epidemiology and End Results (SEER). SEER stat fact sheets: acute myeloid leukemia [Internet]. [cited 2019 Feb 21] Available from: http://seer.cancer.gov/statfacts/html/amyl.html.
4. G Juliusson, J Abrahamsson, V Lazarevic, et al., for the Swedish AML Group and the Swedish Childhood Leukemia Group. Leukemia. 2017 Mar; 31(3): 728–731.
5. Lin et al.  Clin Med Insights Oncol. 2012; 6:205-217 
6. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Blood. 2017 Jan;129(4):424-47.
7. National Cancer Institute. Adult acute myeloid leukemia treatment (PDQ®)-Patient Version. http://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq
8. Rydapt (midostaurin) Summary of Prodcut Characteristics
9. Swedish AML gudlines WWW.sfhem.se/riktlinjer 

 

 

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