“Standard to care” refers to the best-known treatment. In cancer care, a multidisciplinary team where different doctors work together to bring out an overall treatment plan for the patient.
Treatments recommendations depend on many factors:
- The size, grade and type of tumour
- Whether the tumour is applying pressure on vital parts of the brain
- If the tumour has increased to other parts of the body
- Possible side effects
- The patient’s preferences and overall health
Targeted therapy aims at any factor contributing to the growth and development of cancer cells. It can be a specific protein, gene or tissue environment. This treatment blocks the growth and spread of tumour cells while limiting damage to healthy cells.
All cancers do not have the same targets. To find the most effective treatment, the doctor may run tests to identify the genes, proteins, and other factors involved in your leukemia. This helps doctors match each patient with the most effective treatment possible. Additionally, research studies find more about specific molecular targets and treatments directed at them.
For CML, the target is the BCR-ABL tyrosine kinase enzyme protein. The tyrosine kinase inhibitors or TKIs are drugs that target the BCR-ABL tyrosine kinase enzyme. These drugs can stop the BCR-ABL enzyme from working, which causes the CML cells to die faster.
It is noteworthy that men and women taking TKIs should avoid becoming pregnant or fathering a child while taking the drugs because of a risk to the developing child. These drugs can cause liver inflammation, a problem for people who have hepatitis. Before starting treatment with any of these drugs, patients must test for hepatitis. In addition, some TKIs may interact with vitamins, certain foods, or supplements. Talk to the health care team about what foods, vitamins, or supplements you need to avoid. If a patient experiences any side effects, another TKI can be used instead.
Types of TKIs
There are currently 5 TKIs available for CML-
In 2001, Imatinib was the first targeted therapy approved by the (FDA) for CML. It is taken as a pill once or twice per day. It works better than chemotherapy and causes fewer side effects. Almost all patients with chronic phase CML have their blood counts return to standard levels, and their spleen shrinks after receiving this drug. Most importantly, 80% to 90% of patients diagnosed newly with chronic phase CML who receive Imatinib no longer have detectable levels of cells with the Philadelphia chromosome. Imatinib can also be used to treat other types of cancer, like acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome.
The chances of developing resistant CML once it completely responds to Imatinib is shallow. Patients with fewer numbers of cells with the Philadelphia chromosome remaining will stay in the chronic phase longer by taking Imatinib than they might have with the previous treatments. It is very soon to know how long these responses will last or if patients will be cured with this medication alone. However, many patients have been treated with Imatinib since the first clinical trials who still have no detectable cells with the Philadelphia chromosome.
The side effects of Imatinib are mild but may include stomach pain, which is very uncommon. There can be fluid retention, taken with food, swelling around the eyes, fatigue, diarrhoea, and muscle cramps.
The FDA approves dasatinib as an initial treatment for newly-diagnosed chronic phase CML patients and when other drugs are not working. Depending on the dose, the pill can usually be for once a day or sometimes twice a day. The side effects include anaemia, a low level of white blood cells called neutropenia, a low level of platelets called thrombocytopenia, and lung problems containing fluid around the lung or pulmonary hypertension. The doctor will monitor the patient’s blood count frequently after starting dasatinib and temporarily adjust the dose or stop giving the drug if the patient’s blood count drops too low.
Dasatinib may also cause bleeding, fluid retention, diarrhoea, rash, headache, fatigue, and nausea. Dasatinib requires absorption of stomach acid, so patients should not take anti-acid medications.
The FDA also approves nilotinib as an initial treatment for newly-diagnosed chronic phase CML patients and when other drugs are not working. It is a capsule taken by mouth twice per day on an empty stomach. Common side effects include rash, headache, low blood counts, nausea, diarrhoea, and itching. Other possible but severe uncommon side effects include high blood sugar levels, fluid build-up, and pancreas or liver inflammation.
The most severe side effect of nilotinib includes possibly life-threatening heart and blood vessel problems that can lead to narrowing of the blood vessels, stroke, an irregular heartbeat, and possible sudden death. These side effects are usually very rare, but patients may require testing to check their heart health during treatment. There can be interactions with other medications that can increase these risks, so be sure to talk to a doctor about all medications you are taking.
In 2012, bosutinib was approved by the FDA to treat CML when one of the other TKIs was not effective or if a patient experienced too many side effects. The most common side effects include nausea and vomiting, diarrhoea, low levels of blood cells, abdominal pain, fatigue, fever, allergic reactions, and liver problems.
Ponatinib was also approved by the FDA in 2012 for patients when 1 of the other TKIs was ineffective or if a patient experienced too many side effects. The ponatinib also targets CML cells with a particular mutation, known as T315I, which makes these cells resistant to other currently approved TKIs.
The most common side effects include rash, high blood pressure, dry skin, constipation, fever, joint pain, abdominal pain, fatigue, headache, and nausea. Ponatinib may also cause heart problems, blood clots, severe narrowing of blood vessels, stroke, or liver problems.
Measuring treatment effectiveness of TKIs
Patients receiving a TKI should have regular check-ups with the health care team to see how well the treatment is working. To start, these tests are typically done every three months during the first year of treatment. The response of CML includes-
Complete hematologic response
- No signs of abnormal blood cells, such as blasts, in the blood
- Healthy levels of white blood cells and platelets
- The spleen is normal and cannot be felt on a physical exam.
- There are no symptoms of CML.
- The spleen may still be enlarged.
- Blood counts are still abnormal.
- Blood test results and symptoms have improved since treatment started.
- There may still be some blasts in the blood.
These responses can change with time, and there is a risk that the CML will worsen without effective treatment. Sometimes it means continuing on the present TKI to see if the treatment helps further, or it can mean changing to another TKI.
Other tests are used to find the Philadelphia chromosome count cells or contain the BCR-ABL fusion gene. When CML is diagnosed, the Philadelphia chromosome is found in nearly all of a person’s blood cells and bone marrow. Once a person’s CML shows complete hematologic response, the doctor then looks for a cytogenetic response with tests like FISH.
- A complete cytogenetic response means no cells with the Philadelphia chromosome found on the regular cytogenetic tests.
- A partial cytogenetic response means that around 1% and 35% of the cells still have the Philadelphia chromosome.
- A minor cytogenetic response shows that more than 35% of the cells still have the Philadelphia chromosome.
A molecular response can be checked when the PCR test finds the BCR-ABL fusion gene.
- A significant molecular response means that a minimal number of cells (more than 1,000 times fewer than diagnosed) with the BCR-ABL fusion gene are found in the peripheral blood or bone marrow.
- A complete molecular response means no cells with the BCR-ABL fusion gene are found in the peripheral blood or bone marrow.
A vital initial goal of treatment is to achieve a complete cytogenetic response. This may require another bone marrow biopsy if it is unclear whether the drug is working. Or, another bone marrow biopsy may be necessary after 6 to 12 months of treatment to confirm a cytogenetic response. It is unclear whether any of these drugs can cure CML. The disease may return if treatment ends. If treatment with 1 of these drugs works, a patient no longer has evidence of cells with the Philadelphia chromosome in the bone marrow and normal blood cell levels. This is called complete cytogenetic remission. The patients may have to take these drugs throughout their lives to prevent the CML from recurrence. Recent research suggests that some patients may stop treatment after a deep and stable response safely.
More sensitive blood tests, such as PCR and occasionally FISH, are usually done every three months on a blood sample after a person has a cytogenetic response in the bone marrow cells. Patients with no cells with the Philadelphia chromosome on regular cytogenetic tests often need PCR testing to find a molecular response. Patients with a rapid decrease in the number of cells with the Philadelphia chromosome by three months after starting treatment may have the best long-term outcomes.
The most sensitive test to see for remaining CML is known as the quantitative reverse transcriptase PCR (Q-RT-PCR) test. This test is suggested every three months on a blood sample. Generally, this test can find one CML cell remaining among 1 million healthy blood cells. When this test is negative, the CML is likely nearly gone. On the other hand, if a person continues taking the medication as told and the test results begin to rise, the current treatment is not working. This means that it may be time to switch medications before the disease worsens.
A TKI can stop working if the CML develops resistance to it. One reason resistance can occur is if patients don’t take their medication regularly, as prescribed, so it is essential for patients to take their medication as prescribed. Even if patients take the medication correctly, CML may still become resistant to a TKI, so it is vital to receive regular monitoring with cytogenetic testing, FISH, or PCR to see how well the drug continues to work.
Both nilotinib and dasatinib have been shown to bring about a complete cytogenetic response earlier and in more people newly diagnosed with CML than Imatinib. However, Imatinib has been used for a longer time. There is no difference in overall survival when using Imatinib or another TKI as initial treatment. Ponatinib and bosutinib are newer drugs, but both have also produced complete cytogenetic responses in CML people. Because of possible severe side effects, caution and careful monitoring are necessary if ponatinib is suggested after other drugs have stopped working. But, ponatinib is the only TKI that works for patients whose CML cells have the T315I mutation. If the medication you started with stops working, the dose may be increased, or a different TKI may be used instead.
CML being treated with a TKI over the long term may be called chronic cancer.
Chemotherapy uses medicine to kill or stop the growth of cancerous cells. The type of chemotherapy depends upon the stage of cancer. The point that makes a difference is how the chemotherapy enters the body and which cells it affects.
A chemotherapy schedule usually consists of a certain number of cycles over a fixed period. A patient can be given one drug at a time or a combination of different drugs given simultaneously.
A drug called hydroxyurea (Hydrea, Droxia) is often given to lower the levels of white blood cells until CML can be diagnosed. Given capsule form, this drug works well to return blood cells to standard levels within a few days or weeks and reduce the spleen size, but it does not reduce the percentage of cells with the Philadelphia chromosome and does not prevent the blast phase alone. Although hydroxyurea has some side effects, most patients newly diagnosed with chronic phase CML receive Imatinib or another TKI as soon as possible. This means that they don’t need hydroxyurea or use it for only a short time. Chemotherapy side effects depend on the specific drug and the dosage and usually become less severe.
The drug omacetaxine mepesuccinate (Synribo) was approved by the FDA in 2012 for patients with chronic or accelerated phase CML that does not respond to the TKIs mentioned above. Omacetaxine is given by injection under the skin daily for 7 to 14 days. The most common side effects are thrombocytopenia, anaemia, neutropenia, diarrhoea, nausea, fatigue, weakness, skin irritation, fever, and infection.
Immunotherapy, a type of biological therapy, uses artificial or natural substances to harness our immune system to fight.
It uses materials formed either by the body or in a laboratory to improve, target, or restore immune system function.
Interferon (Alferon, Infergen, Intron A, Roferon-A) is immunotherapy. It can reduce the levels of white blood cells and sometimes decrease the number of cells with the Philadelphia chromosome.
Interferon is given daily or weekly by an injection under the skin. It occasionally causes flu-like side effects, like fever, fatigue, chills, and loss of appetite. When given on an ongoing basis, it can also cause memory changes and energy loss. Interferon was the primary treatment for chronic phase CML before Imatinib became available. However, research has shown that TKIs work better to treat CML and cause fewer side effects; hence interferon is no longer suggested as the first treatment for CML. Unlike TKIs, interferon is safe to use in pregnancy.
Stem cell Transplantation/Bone marrow Transplantation
A stem cell transplant is a medical process in which bone marrow that contains the cancer is replaced by highly specialized cells. These cells, known as hematopoietic stem cells, develop into the healthy bone marrow. Hematopoietic stem cells are the blood-forming cells found in the bloodstream and the bone marrow. These stem cells form all of the healthy cells in the blood. Presently, this procedure is more commonly called a stem cell transplant than a bone marrow transplant because it is the stem cells in the blood typically being transplanted, not the actual bone marrow tissue.
Before suggesting transplantation, doctors talk to the patient and family members regarding the risks of this treatment. They will also consider several other factors, like age and general health, cancer type, and previous treatment results.
There are two types of stem cell transplantation depending on the source of the replacement blood stem cells – autologous (AUTO) and allogeneic (ALLO). AUTO uses the patient’s stem cells, while ALLO uses donated stem cells. In both types, the goal is to destroy all cancer cells in the blood, marrow, and other body parts using high doses of chemotherapy or radiation therapy and then allow replacement blood stem cells to create healthy bone marrow.
Only ALLO transplants are used for the treatment of CML.
Side effects depend on the child’s general health, the type of transplant, and other factors.
Cancer and its treatment have side effects that can be mental, physical or financial and managing the effects are palliative or supportive care.
Palliative care includes medication, nutritional changes, emotional and spiritual support and other relaxation therapies.
Palliative care focuses on alleviating how you feel during treatment by managing symptoms and supporting patients and their families with other non-medical needs. Regardless of type and stage of Cancer age, any person may receive this type of care.
Treatment by phase
The immediate goal of treatment is to decrease symptoms of CML. The longer-term goals are to reduce or eliminate the cells with the Philadelphia chromosome to slow down or prevent the disease from moving to the blast phase. Treatment will often first include a TKI. An ALLO stem cell transplantation will only be considered if TKI treatment does not work.
The drugs used for chronic phase CML can also be used for accelerated phase CML. Although TKI treatment can work well for accelerated phase CML, it is less likely to work as well as it does for chronic phase CML. Nilotinib or dasatinib are more effective in providing longer remissions, but many patients have the CML return within about two years. Therefore, an ALLO stem cell transplantation should be reviewed if possible. If an ALLO stem cell transplantation is not suggested or a matched donor cannot be found, the treatment plan may include a different TKI or a clinical trial.
Treatment with a TKI works well only for a few months for patients in the blast phase, but it can help control the CML while a stem cell or bone marrow transplant is being arranged. The long-term results are better if the transplant can be done while dasatinib or Imatinib is working. Stem cell or bone marrow transplantation in the blast phase is less successful than in the chronic phase, but this approach has worked well for some patients. Many people with CML in the blast phase receive Imatinib or dasatinib plus chemotherapy similar to that used for patients with acute leukemia, such as acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The chance of remission from this approach is approximately 20% to 30%, although leukemia comes back for most patients within weeks to a few months. Hydroxyurea is usually given to patients to help control blood cell levels. If stem cell or bone marrow transplantation is not an option, your doctor may recommend a clinical trial.
- Resistant CML
Refractory CML occurs when complete remission is not achieved because the drugs did not destroy enough leukemia cells. These patients usually continue to have low blood counts, need transfusions, and risk bleeding or infection.
Remission and chance of recurrence
Remission is when cancer is no longer detectable in the body and there are no symptoms. This may be called having ‘no evidence of disease’. A remission can be temporary or permanent. Many people worry about the recurrence of cancer. The doctor performs another round of tests to know the extent of the recurrence. Mainly the treatment plan includes the treatments explained above, like surgery, chemotherapy, radiation therapy, and targeted therapy.
Care and Concern
It is vital to have straightforward conversations with your health care team to express your feelings, preferences, and concerns. The health care team has unique skills, knowledge, and experience to assist patients and their families. Ensuring that a person is physically comfortable, free from pain, and emotionally supported is extremely important.