What are the Treatment Options for Advanced or “Blast” Phase Chronic Myeloid Leukemia?

Chronic myeloid leukemia is an acquired disease from a gene mutation and is neither inherited (passed down from generation to generation) nor contagious. Although the reason behind this mutation remains unknown, some scientific data support some risk factors may increase your chances of getting chronic myeloid leukemia:

• Age the older you are, the higher your chances
• Gender Men are more susceptible to CML
• Exposure to radiation

Phases of Chronic Myeloid Leukemia

Chronic myeloid leukemia is classified into three phases that helps predict outcome. The phases are based mainly on the number of immature white blood cells (blasts) in the blood or bone marrow. Most patients are diagnosed with CML at the chronic phase when there are no significantly noticeable symptoms through routine checkups and abnormal blood work.

• Chronic phase: Approximately 85% of people are in the chronic phase of CML when they are initially diagnosed. In chronic phase CML, there are less than 5 percent immature leukemic blast cells (the abnormal white blood cells) in the bone marrow. Chronic phase CML is well controlled with oral medications in nearly all cases. Left untreated, patients will eventually progress to the accelerated or blast phase. However, this can take years to happen.
• Accelerated phase: During the accelerated phase, the white blood cells become increasingly unable to mature normally, and there are between 10% 20% leukemic blast cells in the blood or bone marrow. In this phase, symptoms like night sweats, fatigue, weight loss, and frequent infections start to manifest more clearly as the number of blast cells starts to increase. Accelerated phase CML is more difficult to control with medications, probably because of new mutations that develop in the CML cells. This stage can take from three to nine months. Similarly, if left untreated patients will progress to the blast phase.
• Blast phase: In blast phase of CML (also called "blast crisis"), there are more than 20% blast cells in the blood or bone marrow. This is the last phase of chronic myeloid leukemia and leukemia has become more aggressive with noticeable symptoms. This phase is also called the 'blast crisis'. CML can progress to blast phase from the chronic or accelerated phase, or in some cases a person is already in the blast phase at the time of diagnosis. Blast phase CML is difficult to control with medications. Unfortunately, at the blast phase if patients aren't treated it's most likely fatal.

Dr. Javier Pinilla, a hematologist/oncologist at Moffitt Cancer Center, points out that treatment with TKIs is often less successful in the accelerated and blast phases because of the progression of the disease.

“Think about an evolution of the disease. Chronic phase is where the patient is stable. Accelerated starts to really get hot, and, somewhat, is the worst prognosis. And the blast phase is exactly like an acute myeloid leukemia,” Dr. Pinilla explains, adding that patients in the blast phase are typically treated in a similar way that doctors would treat an acute (or fast-growing) leukemia.

Most Common Treatments

The main treatment for CML are targeted cancer drugs (such as tyrosine kinase inhibitors). Other possible treatments include chemotherapy and a stem cell transplant.

• Targeted Treatment: For most people, CML is treated with an oral medication, called a tyrosine kinase inhibitor (TKI). The rates of progression have reduced significantly from over >20% in the pre-TKI era to <5% now, largely due to refinements in CML therapy and response monitoring. This medication blocks the effects of BCR::ABL1 (the abnormal protein found in people with CML). Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase.
• Chemotherapy: Drugs that carry toxic substances that inhibit the cancer cells. These are mostly used when TKIs aren't effective, or they cause intolerable side effects. (ex. omacetaxine).
• Stem cell transplantation: Also called bone marrow transplantation is usually used after the disease stops responding or relapses during treatment with a TKI.

Treatment of Later Stages

Responses to targeted therapy are considerably less favorable in the accelerated/blast phase than in chronic phase. Although most patients will have an initial response to tyrosine kinase inhibitors most people in accelerated or blast phase will eventually relapse if they are treated with a TKI alone, especially if they develop while on treatment with a TKI. If the patient is already getting a TKI, the dose may be increased. Another option is to switch to other TKIs.

The most well know TKI is called Imatinib (brand name Gleevec). As mentioned above, most patients in the acccelerated phase respond to treatment with Imatinib, but the responses do not seem to last as long as they do in patients in the chronic phase. Other newer TKIs could also be used in this phase:

• Asciminib (brand name: Scemblix).
• Dasatinib (brand name: Sprycel)
• Nilotinib (brand name: Tasigna)
• Bosutinib (brand name: Bosulif)
• Ponatinib (brand name: Iclusig)

Sometimes the CML cells are tested to see if they have genetic changes (mutations) that may mean that a certain TKI is more or less likely to work.

T315I mutation

Some patients with CML develop a gene change called the T315I mutation that keeps most of the TKIs from working.  Patients with this mutation may be treated with Ponatinib (brand name: Iclusig) or Asciminib (brand name: Scemblix) and are generally encouraged to consider transplantation.

Chemotherapy

Omacetaxine (brand name: Synribo) is a form of chemotherapy that is given as an injection under the skin daily for two weeks, and repeated every four weeks for a maximum of six cycles. It’s a treatment option for adults with chronic or accelerated phase CML with resistance to and/or intolerance to two or more TKIs.

Omacetaxine can be used to treat all mutations resistant to TKIs including the T315I mutation. In general, its use is limited to patients who have exhausted all other TKI options and who are not candidates for allogeneic transplant.

Side effects of omacetaxine include infection, diarrhea, nausea, fever, and fatigue.

Stem cell transplantation

Stem cell transplantation replaces diseased bone marrow cells with healthy bone marrow. For CML, this requires an allogeneic transplant (healthy stem cells donated by another person). The transplanted stem cells generate a new immune system for the person with CML, which recognizes the leukemia cells as foreign and attempts to destroy them. This beneficial reaction against the CML cells is called the graft-versus-tumor effect.

In CML, the chances of successfully controlling CML with stem cell transplantation are related to your age and the phase of disease at the time of the transplant. Younger patients generally tolerate transplantation better than older patients. Transplantation is also more likely to be successful when CML has been restored to chronic phase. Most people will be treated with a TKI before transplantation with the hope of restoring accelerated or blast phase CML to chronic phase.

Clinical Trials

A clinical trial is a research study involving volunteers that looks into using new drugs or therapies. The goal of these studies is to test if new treatments are safe and effective. Clinical trials are a personal decision that should be discussed with your doctor to consider whether you would benefit from a new drug therapy, and other considerations like distance to trial and travel time.

Clinical trials can be an option for people with cancer at many points during the treatment process. Your doctor may have spoken with you about possibly enrolling in a trial if you have advanced disease or if there's a drug that's currently considered investigational that may work better than the standard for you.

A lot of patients may feel uncomfortable about the thought of participating in a trial, but the trials can provide amazing opportunities for patients. For one thing, they give patients access to a bevy of new drugs that are currently being developed by pharmaceutical companies.

Here at SurvivorNet, it's our goal to help cancer patients make the most informed decisions when it comes to their health. Sometimes, joining a clinical trial is a good decision.

How Valuable Are Second Opinions?

Once you've gone through all of the tests needed to diagnose your cancer and your doctor has recommended a course of action, you will likely, finally, feel a sense of resolution. But no matter how qualified and experienced the doctor who diagnosed you is, there may be a lingering feeling about getting a second opinion. It's OK to consider your doctor's treatment recommendations as just the first step in figuring out what to do next.

A second opinion gives you the chance to explore other therapeutic options. Another doctor may offer a new perspective on your cancer, and possibly recommend treatments that are different than what the first doctor you saw suggested.

Seeking advice from a different doctor can also help ease any fears you might have about whether you're on the right treatment path. A study showed that more than one-third of cancer patients sought a second opinion, and nearly 80% felt more assured after doing so.

Questions to Ask Your Doctor

• How do I know at which CML phase I am?
• How can I prevent my CML in advancing to other phases?
• What’s the best treatment for me?
• Am I eligible to receive TKIs or a stem cell transplant?
• Should I be tested for T315I mutation?
• Should I get a second option regarding my treatment?

Learn more about SurvivorNet's rigorous medical review process.

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