acute myeloid leukemia with mutated NPM1

Acute Myeloid Leukemia (AML) with Mutated NPM1

AML with mutated NPM1 is a subtype of AML characterized by mutations in the Nucleophosmin 1 (NPM1) gene. This genetic alteration occurs in about one-third of AML cases and is specific to this type of leukemia.

Key Features:

• Genetic Alteration: Mutations in exon 12 of the NPM1 gene, which results in aberrant cytoplasmic expression of NPM1.
• Frequency: Occurs in approximately 30-35% of adult AML cases and more than 50% of pediatric AML cases.
• Association with Other Mutations: Frequently associated with FLT3-ITD, DNMT3A, and other mutations.

Clinical Implications:

• Treatment Outcome: Studies have shown that patients with NPM1-mutated AML tend to have a better treatment outcome compared to those without this mutation.
• Remission Status: The presence of the NPM1 mutation can disappear once in remission, but its persistence may indicate a higher risk of relapse.

Genomic Landscape:

• FLT3 Mutations: The most frequently mutated gene in NPM1-mutant AML is FLT3, with ITD mutations being the most common.
• Other Genes: Other genes, such as DNMT3A and ASXL1, are also commonly mutated in this subtype of AML.

References:

• [2] NPM1 mutations occur in about one-third of AML, are AML-specific, usually involve exon 12 and are frequently associated with FLT3-ITD, DNMT3A, ...
• [7] NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30–35% of adult AML and more than 50% ...
• [5] The majority of NPM1 mutations reported affect exon 12 (classic type A mutation), accounting for 75–80% of adult NPM1-mutated AML cases, which ...

Acute myeloid leukemia (AML) with mutated NPM1 can present a range of signs and symptoms, which are often nonspecific and similar to those found in other types of AML. Some common symptoms include:

• Fatigue and weakness [14]
• Fever [13]
• Frequent infections [13]
• Bruising or bleeding due to easy bruising or bleeding [1], [10]
• Bone pain [13]

These symptoms occur as a result of the leukemic infiltration of bone marrow, leading to cytopenia. It's essential to note that not everyone with AML will experience all of these symptoms, and some may have no symptoms at all.

In addition to these general symptoms, AML with mutated NPM1 can also be characterized by:

• Anemia [1]
• Bone marrow failure [1]

It's worth noting that the diagnosis of AML with mutated NPM1 typically involves a combination of clinical evaluation, laboratory tests, and bone marrow aspiration and biopsy, as well as genetic testing to identify the mutation.

References: [1] - Signs and Symptoms [10] - Risk factors for acute myeloid leukemia [13] - The signs and symptoms of AML are diverse and nonspecific, but most of them are mainly attributed to the resulting cytopenia caused by leukemic infiltration of bone marrow. [14] - AML with NPM1 Mutation may present signs and symptoms similar to other types of AML.

Diagnostic Tests for Acute Myeloid Leukemia (AML) with Mutated NPM1

Acute myeloid leukemia (AML) is a type of cancer that affects the blood and bone marrow. In some cases, AML can be caused by mutations in the Nucleophosmin 1 (NPM1) gene. Detecting these mutations is crucial for accurate diagnosis and treatment planning.

Molecular Techniques

Several molecular techniques are used to detect NPM1 mutations in AML patients:

• Western Blot Assay: This technique uses antibodies that specifically recognize mutated NPM1 proteins, but not the wild-type protein (2). The Western blot assay is a sensitive and specific method for detecting NPM1 mutations.
• Genetic Testing: Genetic testing can identify NPM1 mutations in AML patients. This involves analyzing DNA samples from bone marrow or blood cells to detect any genetic abnormalities (7).

Immunohistochemistry (IHC)

Immunohistochemistry is another diagnostic method used to detect NPM1 mutations:

• IHC Detection of NPM1c+: IHC detection of NPM1c+ is a simple, low-cost, and highly sensitive method for diagnosing AML with mutated NPM1 (5). This technique can serve as a surrogate marker for detecting NPM1 mutations.

Minimal Residual Disease (MRD) Testing

MRD testing is used to detect any remaining cancer cells after treatment. In the case of AML with mutated NPM1, MRD testing can help identify whether AML cells are still present in the body (4).

Other Diagnostic Methods

Other diagnostic methods for AML include:

• Immunophenotyping: This technique involves analyzing the surface markers on cancer cells to determine their type and origin.
• Genetics Data: Analyzing genetics data from bone marrow or blood samples can provide information about genetic abnormalities, including NPM1 mutations (7).

References

(2) B Falini · 2010 · Cited by 44 — Detection of NPM1 mutated proteins by Western blot.

(4) Oct 4, 2024 — Minimal residual disease (MRD) testing helps check for any remaining cancer cells after treatment and can also help identify whether AML cells are still present in the body.

(5) IHC detection of NPM1c+ is a simple, low-cost, very sensitive, and specific alternative assay to diagnose NPM1-mutated AML (26).

(7) Definitive Diagnostic Methods. Genetic testing. Immunophenotyping. Genetics Data. del(9q). Gain of chromosome 8. Mutated NPM1. Immunophenotyping. CD13+.

Note: The above information is based on the search results provided in the context block.

Treatment Options for Acute Myeloid Leukemia (AML) with Mutated NPM1

Acute myeloid leukemia (AML) is a type of blood cancer that can be challenging to treat. In patients with mutated NPM1, the standard therapy includes "3+7" induction chemotherapy and consolidation therapy [1]. However, there are other treatment options being explored.

Targeted Therapies

One promising targeted therapy for NPM1-mutated AML is ziftomenib, which has shown promise in late-stage trials [2]. Ziftomenib targets the mutated NPM1 protein, making it a potential game-changer in treating this type of AML. The FDA has granted breakthrough therapy designation to ziftomenib for the treatment of NPM1-mutant acute myeloid leukemia [3].

Combination Therapies

In addition to targeted therapies, combination treatments are also being explored. For example, venetoclax plus menin inhibitor has been shown to be superior to the menin inhibitor alone in eliminating leukemic cells in mouse models of NPM1-mutated/FLT3-ITD AML [4]. Another combination therapy is gemtuzumab ozogamicin plus chemotherapy, which has been effective in treating NPM1-mutated AML [5].

Other Treatment Options

Other treatment options for NPM1-mutated AML include FLT3 inhibitors, engineered T-cells, and menin inhibitors. These treatments are still being researched and may offer additional hope for patients with this type of AML [6][7].

In summary, while "3+7" induction chemotherapy and consolidation therapy remain the standard treatment for NPM1-mutated AML, targeted therapies like ziftomenib and combination treatments such as venetoclax plus menin inhibitor are being explored as potential new options.

References:

[1] Wang R. (2022) The standard therapy of NPM1-mutated AML patients includes “3+7” induction chemotherapy and consolidation therapy.

[2] Jun 12, 2024 Kura Oncology's ziftomenib for NPM1-mutated AML shows promise and is entering late-stage trials.

[3] Apr 22, 2024 The FDA has granted breakthrough therapy designation to ziftomenib for the treatment of NPM1-mutant acute myeloid leukemia.

[4] by R Ranieri · 2022 · Cited by 58 In mouse models of NPM1-mutated/FLT3-ITD AML, venetoclax plus menin inhibitor was superior to the menin inhibitor alone, in eliminating leukemic cells.

[5] Jul 13, 2023 Eunice S. Wang, MD, shares first-line treatment approaches for patients with NPM1-mutant AML, discussing current clinical data.

[6] Oct 4, 2024 Treatments for NPM1 Mutated AML · Venetoclax + HMAs · Gemtuzumab ozogamicin + chemotherapy · FLT3 inhibitors · Engineered T-cells · Menin inhibitors.

[7] Treatments for NPM1-mutated acute myeloid leukemia​​ Treatments for NPM1-mutated AML include: Chemotherapy: Many drugs stop cancer growth or destroy cancer cells ...

Understanding Differential Diagnosis in AML with Mutated NPM1

Differential diagnosis refers to the process of distinguishing between different possible causes or conditions that may present with similar symptoms or characteristics. In the context of Acute Myeloid Leukemia (AML) with mutated NPM1, differential diagnosis is crucial for accurate diagnosis and treatment.

Key Considerations in Differential Diagnosis

• Presence of clonal hematopoiesis (CH)-associated mutations: The presence of persistent CH-associated mutations can be a confounding factor for Minimal Residual Disease (MRD) assessment in AML with mutated NPM1 [5].
• Normal karyotype and absence of FLT3 internal tandem duplication mutation: AML with mutated NPM1, normal karyotype, and absence of FLT3 internal tandem duplication mutation has a characteristically favorable prognosis [8].
• Distinguishing features from other subtypes of AML: Differential diagnosis in AML with mutated NPM1 involves distinguishing it from other subtypes of AML, such as those with mutations in the FLT3 gene or normal karyotype.

Clinical Implications

Accurate differential diagnosis is essential for determining the most appropriate treatment plan and prognosis for patients with AML with mutated NPM1. It requires a thorough understanding of the molecular and genetic characteristics of this subtype of AML, as well as its clinical implications.

References

• [3] by B Falini · 2021 · Cited by 35 — 6: Differential diagnosis of NPM1-mutated AML.
• [8] Jun 21, 2024 — AML with mutated NPM1, normal karyotype and absence of FLT3 internal tandem duplication mutation has characteristically favorable prognosis.