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Chronic Myeloid Leukemia

Disease Details

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Description: Chronic myeloid leukemia (CML) is a type of blood cancer that starts in the bone marrow's blood-forming cells and is characterized by the uncontrolled growth of myeloid cells.
Type: Chronic myeloid leukemia (CML) is primarily a clonal bone marrow stem cell disorder. The type of genetic transmission for CML is not hereditary; it is typically caused by a specific genetic mutation known as the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22. This mutation is acquired during a person's lifetime and is not passed from parent to child.
Signs And Symptoms: The way CML presents depends on the stage of the disease at diagnosis as it has been known to skip stages in some cases.Most patients (~90%) are diagnosed during the chronic stage which is most often asymptomatic. In these cases, it may be diagnosed incidentally with an elevated white blood cell count on a routine laboratory test. It can also present with symptoms indicative of hepatosplenomegaly and the resulting left upper quadrant pain this causes. The enlarged spleen may put pressure on the stomach causing a loss of appetite and resulting weight loss. It may also present with mild fever and night sweats due to an elevated basal level of metabolism.Some (<10%) are diagnosed during the accelerated stage which most often presents bleeding, petechiae and ecchymosis. In these patients fevers are most commonly the result of opportunistic infections.Some patients are initially diagnosed in the blast phase in which the symptoms are most likely fever, bone pain and an increase in bone marrow fibrosis.
Prognosis: Before the advent of tyrosine kinase inhibitors, the median survival time for CML patients had been about 3–5 years from time of diagnosis.With the use of tyrosine kinase inhibitors, survival rates have improved dramatically. A 2006 follow-up of 553 patients using imatinib (Gleevec) found an overall survival rate of 89% after five years.A 2011 followup of 832 patients using imatinib who achieved a stable cytogenetic response found an overall survival rate of 95.2% after 8 years, which is similar to the rate in the general population. Fewer than 1% of patients died because of leukemia progression.
Onset: Chronic myeloid leukemia (CML) typically has a gradual onset and may not present noticeable symptoms in its early stages. As the disease progresses, it can lead to symptoms such as fatigue, weight loss, night sweats, fever, and an enlarged spleen. Early detection is often incidental through routine blood tests showing elevated white blood cell counts.
Prevalence: Chronic myeloid leukemia (CML) is relatively rare, with an annual incidence of about 1 to 2 cases per 100,000 people globally. The prevalence is higher due to the chronic nature of the disease and advances in treatment that have improved survival rates.
Epidemiology: Chronic Myeloid Leukemia (CML) is a type of cancer that affects the bone marrow and blood.

Epidemiology:
- CML accounts for about 15-20% of all adult leukemias.
- The annual incidence rate is approximately 1-2 cases per 100,000 individuals.
- CML is more common in adults, with the median age of diagnosis around 60-65 years.
- It is slightly more prevalent in males than in females.
- The disease is rare in children, being primarily an adult disease.
- Risk factors include exposure to ionizing radiation and, though rarely, having a family history of CML.

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Intractability: Chronic myeloid leukemia (CML) is not considered intractable due to advances in treatment, particularly with the use of tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib. These treatments have significantly improved prognosis, allowing many patients to achieve long-term remission and manage the disease effectively. However, treatment requires ongoing medical supervision and can involve side effects, and not all patients may respond optimally to available therapies.
Disease Severity: Chronic Myeloid Leukemia (CML) is generally considered a serious condition, but its severity can vary based on the disease phase and response to treatment. It progresses through three phases:

1. Chronic Phase: Most patients initially present in this phase, which is typically more manageable with targeted therapies like tyrosine kinase inhibitors (TKIs). Many patients can achieve remission and maintain a good quality of life.

2. Accelerated Phase: The disease progresses with an increased number of abnormal cells. It is more challenging to control and may require more aggressive treatment strategies.

3. Blast Phase (or Blast Crisis): The most severe phase, where CML behaves like an acute leukemia with a high risk of complications, leading to a poor prognosis.

The introduction of targeted therapies has significantly improved outcomes, allowing many patients to live longer, healthier lives.
Healthcare Professionals: Disease Ontology ID - DOID:8552
Pathophysiology: CML was the first cancer to be linked to a clear genetic abnormality, the chromosomal translocation known as the Philadelphia chromosome. This chromosomal abnormality is so named because it was first discovered and described in 1960 by two scientists from Philadelphia, Pennsylvania, US: Peter Nowell of the University of Pennsylvania and David Hungerford of Fox Chase Cancer Center.In this translocation, parts of two chromosomes (the 9th and 22nd) switch places. As a result, part of the BCR ("breakpoint cluster region") gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal "fusion" gene generates a protein of p210 or sometimes p185 weight (p210 is short for 210 kDa protein, a shorthand used for characterizing proteins based solely on size). Because abl carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the bcr-abl fusion gene product is also a tyrosine kinase.
The fused BCR-ABL protein interacts with the interleukin 3beta(c) receptor subunit. The BCR-ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn, BCR-ABL activates a cascade of proteins that control the cell cycle, speeding up cell division. Moreover, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. With improved understanding of the nature of the BCR-ABL protein and its action as a tyrosine kinase, targeted therapies (the first of which was imatinib) that specifically inhibit the activity of the BCR-ABL protein have been developed. These tyrosine kinase inhibitors can induce complete remissions in CML, confirming the central importance of bcr-abl as the cause of CML.
Carrier Status: Chronic myeloid leukemia (CML) is not typically associated with a "carrier status" as seen in some genetic conditions. CML is a type of cancer that originates in the bone marrow and is usually caused by a specific genetic abnormality known as the Philadelphia chromosome, which involves a translocation between chromosomes 9 and 22. This leads to the production of an abnormal enzyme called BCR-ABL tyrosine kinase. CML is not inherited in a traditional sense, but rather it occurs due to this acquired genetic mutation.
Mechanism: Chronic Myeloid Leukemia (CML) is a type of cancer that affects the bone marrow and blood.

**Mechanism:**
CML is characterized by the uncontrolled proliferation of myeloid cells in the bone marrow, leading to an excess of these cells in the blood.

**Molecular Mechanisms:**
The hallmark of CML is the presence of a genetic abnormality known as the Philadelphia chromosome. This results from a translocation between chromosome 9 and chromosome 22 (t(9;22)(q34;q11)). The translocation creates a fusion gene called BCR-ABL1.

**BCR-ABL1**:
- **BCR**: Breakpoint Cluster Region.
- **ABL1**: A gene on chromosome 9 coding for a tyrosine kinase.

The BCR-ABL1 fusion gene encodes a constitutively active tyrosine kinase enzyme that drives the proliferation of myeloid cells, inhibits DNA repair, and reduces apoptosis (programmed cell death), leading to the accumulation of leukemic cells.

The BCR-ABL1 tyrosine kinase is the primary target for CML treatment, and drugs called tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib) are used to block its activity, thereby controlling the disease.
Treatment: The only curative treatment for CML is a bone marrow transplant or an allogeneic stem cell transplant. Other than this there are four major mainstays of treatment in CML: treatment with tyrosine kinase inhibitors, myelosuppressive or leukapheresis therapy (to counteract the leukocytosis during early treatment), splenectomy and interferon alfa-2b treatment. Due to the high median age of patients with CML it is relatively rare for CML to be seen in pregnant women, despite this, however, chronic myelogenous leukemia can be treated with relative safety at any time during pregnancy with the cytokine interferon-alpha.
Compassionate Use Treatment: Compassionate use treatment for chronic myeloid leukemia (CML) may involve investigational drugs that are not yet approved by regulatory authorities. These treatments are typically accessed when no other viable options exist and the patient does not qualify for clinical trials. Some experimental and off-label treatments include:

1. **Ponatinib**: Although ponatinib is FDA-approved for CML, its use can extend beyond standard treatment indications for specific mutations and resistant cases.
2. **Asciminib**: This is an investigational drug in some regions and may be available through compassionate use programs. It works by targeting the ABL myristoyl pocket.
3. **Bosutinib**: Initially developed for other types of cancer, bosutinib can be used off-label for CML patients resistant to other treatments.
4. **Combination Therapies**: Experimental approaches combining multiple tyrosine kinase inhibitors (TKIs) or adding novel agents to existing TKIs.
5. **Immunotherapies**: Investigational immunotherapy approaches, such as CAR-T cells targeting specific markers on CML cells, are being explored.

It's important to consult with a healthcare professional to explore these options based on the specific case and the regulatory environment.
Lifestyle Recommendations: For chronic myeloid leukemia (CML), lifestyle recommendations include:

1. **Healthy Diet**: Focus on a balanced diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats to maintain overall health and support the immune system.
2. **Regular Exercise**: Engage in regular physical activity, such as walking, yoga, or swimming. Exercise can help improve energy levels, reduce stress, and enhance overall well-being.
3. **Avoid Infections**: Practice good hygiene, avoid crowded places during flu season, and stay up to date with vaccinations to reduce the risk of infections.
4. **Stress Management**: Utilize stress-reducing techniques like meditation, relaxation exercises, and therapy to manage mental and emotional strain.
5. **Quit Smoking and Limit Alcohol**: Smoking and excessive alcohol consumption can negatively impact health. Quitting smoking and limiting alcohol can improve treatment outcomes and overall health.
6. **Regular Medical Check-Ups**: Keep consistent appointments with healthcare providers to monitor the condition and manage any side effects or complications from treatments.
7. **Medication Adherence**: Follow prescribed treatments and medication schedules precisely to manage the disease effectively.

Consult with healthcare professionals for personalized lifestyle recommendations tailored to individual health needs.
Medication: For chronic myeloid leukemia (CML), medications typically used include tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. These drugs target the BCR-ABL protein, which is produced by the Philadelphia chromosome abnormality characteristic of CML. They help to control the proliferation of leukemia cells and are often effective in managing the disease.
Repurposable Drugs: For chronic myeloid leukemia (CML), some drugs used in treatment that have origins or usage in other diseases, i.e., repurposable drugs, include:

1. **Imatinib (Gleevec)** - Originally developed for CML, it has also found applications in treating gastrointestinal stromal tumors (GISTs).
2. **Dasatinib (Sprycel)** - Besides CML, it is used for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).
3. **Nilotinib (Tasigna)** - Similar to dasatinib, it is also effective against Ph+ ALL.
4. **Bosutinib (Bosulif)** - Another tyrosine kinase inhibitor (TKI) used for CML, showing potential in other malignancies.
5. **Ponatinib (Iclusig)** - Effective in treating patients with resistant or intolerant CML and also being explored for other cancers.

Repurposing these drugs can be beneficial for other cancer types and diseases with similar pathophysiological pathways.
Metabolites: Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome resulting in the BCR-ABL1 fusion gene, leading to the production of the BCR-ABL1 protein with enhanced tyrosine kinase activity. This abnormal kinase activity affects several metabolic pathways. Key metabolic alterations in CML include:

1. **Increased Glycolysis**: CML cells exhibit heightened glycolytic activity, akin to the Warburg effect found in many cancers.
2. **Altered Mitochondrial Function**: Dysregulated mitochondrial dynamics and increased oxidative phosphorylation can be observed.
3. **Nucleotide Synthesis**: Enhanced purine and pyrimidine metabolism supports rapid cell proliferation.
4. **Amino Acid Metabolism**: Changes in glutamine and other amino acids metabolism are involved in supporting the energetic and biosynthetic demands of the leukemic cells.

These metabolic changes not only provide insights into the disease's pathophysiology but can also offer potential therapeutic targets.
Nutraceuticals: For chronic myeloid leukemia (CML):

Nutraceuticals: There is no strong clinical evidence that nutraceuticals can treat or cure CML. Some studies suggest that certain dietary components, such as antioxidants, vitamins, and polyphenols, might support overall health or enhance the body's response to conventional treatments, but these should not replace standard medical therapies. Always consult with a healthcare provider before starting any new supplement regimen.

Nanotechnology: Research into nanotechnology for CML is ongoing and shows promise in improving drug delivery and targeting cancer cells more precisely. For instance, nanoparticle-based formulations can potentially enhance the efficacy and reduce the side effects of tyrosine kinase inhibitors (TKIs), the standard treatment for CML. However, these applications are largely experimental and not yet a part of routine clinical practice.
Peptides: Peptides and nanoparticles are areas of active research in the treatment of chronic myeloid leukemia (CML). Peptides can be used to design specific inhibitors that target the BCR-ABL fusion protein, which is the primary driver of CML. Nanoparticles, on the other hand, can serve as delivery systems to transport these peptide inhibitors or other therapeutic agents directly to cancer cells, reducing side effects and improving efficacy.