Acute Myeloid Leukaemia Refractory

Refractory acute myeloid leukaemia is when the disease does not respond to initial treatment, a challenging situation that requires carefully tailored approaches to help patients achieve remission.

Table of contents

• What is refractory acute myeloid leukaemia?
• The importance of achieving complete remission
• Factors that affect treatment planning
• Chemotherapy treatment options
• Targeted therapy approaches
• Stem cell transplantation
• Central nervous system treatment
• Supportive care and emotional wellbeing

What is refractory acute myeloid leukaemia?

Refractory acute myeloid leukaemia (AML) means the leukaemia did not respond to initial treatment. Complete remission has not been reached because the chemotherapy drugs did not kill enough leukaemia cells^[1]. This is different from relapsed AML, where the leukaemia comes back after treatment and remission^[1].

When your first treatment for AML does not get you into remission, this is called refractory AML^[4]. The formal definition describes refractory disease as the inability to attain complete remission (CR) or complete remission with incomplete hematologic recovery after two courses of intensive induction treatment^[10]. However, approximately 10% to 40% of AML patients do not respond to initial therapy and are thus categorized as refractory or resistant to treatment^[5].

Hearing that treatment has not worked is understandably very difficult. You might feel shocked, scared, or devastated^[4]. Both relapsed and refractory AML need more treatment to reach complete remission^[1].

The importance of achieving complete remission

The achievement of complete remission (CR) after receiving induction chemotherapy has historically been considered essential for improving survival in patients with AML^[3]. In a recent study of over 6,000 patients with AML, approximately 90% of patients who were alive three or five years after induction had achieved CR after their initial therapy, independent of the cytarabine dose and age of the patients^[3].

Complete remission is an arbitrarily defined state of reduced disease burden based on morphological assessment of the bone marrow and peripheral blood. While CR is by no means sufficient for achieving cure, achieving CR serves to identify patients that are sensitive to the standard cytotoxic chemotherapeutic agents, particularly cytarabine and the anthracyclines^[3].

Factors that affect treatment planning

Your healthcare team will suggest treatments based on your needs and work with you to develop a treatment plan^[1]. Treatment of refractory AML is based on your individual circumstances, and there are many options available^[19].

Some factors considered for your treatment include:

• Your age
• Your overall health and fitness
• How long the leukaemia was in remission (if applicable)
• What treatments you had before and how you responded to them
• Any side effects you experienced
• Your subtype of AML
• The genetic changes in your leukaemia cells
• Where the leukaemia comes back
• Whether or not you have any other medical conditions
• Your preference on how you wish to be treated

^[1][19]

New treatment plans must be carefully devised after taking into account several factors such as the patient’s age, preference, cytogenetic findings (information about chromosome changes), response to drugs, and molecular profile. Therapy needs to be customized for each patient depending on their specific disease details^[5].

Chemotherapy treatment options

Chemotherapy uses anticancer drugs to destroy cancer cells. Chemotherapy is the main treatment for relapsed or refractory AML^[1]. It may include repeating cycles of the same or similar drugs that were used in induction treatment if the complete remission was longer than one year. Similar or higher doses of the drugs may be used^[1].

A repeat course of the 7-and-3 protocol may be given. In this protocol, cytarabine (Cytosar) is given continuously for seven days with an anthracycline given for three days. The anthracyclines used in this protocol include daunorubicin (Cerubidine), doxorubicin (Adriamycin), idarubicin (Idamycin), and mitoxantrone (Novantrone)^[1].

Other types of chemotherapy combinations that may be offered for relapsed or refractory AML include:

• FLAG – fludarabine (Fludara), cytarabine and filgrastim (Neupogen)
• MEC – mitoxantrone (Novantrone), etoposide (Vepesid) and cytarabine
• High-dose cytarabine (HDAC) and mitoxantrone
• High-dose etoposide and cyclophosphamide (Cytoxan, Procytox)
• Cytarabine, daunorubicin and etoposide
• Clofarabine and cytarabine with or without filgrastim

^[1]

Some people with relapsed or refractory AML are not strong enough to have intensive chemotherapy. If this is the case, you may be offered a less intensive chemotherapy regimen that includes one of these chemotherapy combinations:

• Azacitidine (Vidaza) with or without venetoclax (Venclexta)
• Decitabine (Dacogen, Demylocan, Inqovi) with or without venetoclax
• Clofarabine with or without cytarabine

^[1]

Targeted therapy approaches

Targeted therapy uses drugs to target specific molecules (such as proteins) on cancer cells or inside them to stop the growth and spread of cancer^[1].

Some people with relapsed or refractory AML are not strong enough to have intensive chemotherapy. If this is the case, you may be offered targeted therapy^[1].

If you have AML with the FLT3 mutation, you may be treated with gilteritinib (Xospata). If you have AML with a CD33 protein marker, you may be treated with gemtuzumab ozogamicin (Mylotarg)^[1].

Your medical team will send your samples to look for any new genetic changes in your leukaemia cells. These help your medical team work out the most suitable treatment for you^[19].

Stem cell transplantation

Allogeneic stem cell transplantation is a treatment option for people diagnosed with refractory AML^[5]. Treatment options usually include chemotherapy and a stem cell transplant if possible^[1].

This involves the transfer of stem cells from a healthy donor to the patient’s body after intensive radiation or chemotherapy. This procedure is used to treat high-risk AML patients who do not fully respond to initial treatment or patients in whom a relapse of the disease is found post previous successful treatment^[5].

It can be a risky procedure due to the high-intensity chemotherapy or radiation given prior to stem cell transplantation. Intensive radiation and chemotherapy cause severe side effects and also impair the ability to produce one’s own stem cells. The main objective of this intensive therapy is to deactivate the immune system, thus preparing it to receive new stem cells. It reduces the possibility of graft rejection, kills the remaining cancer cells to prevent a recurrence of cancer, and enables an overall successful transplant^[5].

Progress in supportive care strategies and donor identification has enabled more of these patients to undergo unrelated donor transplantation^[3]. Only a proportion of patients with chemoresistant disease can be salvaged by allogeneic stem cell transplantation^[3].

Central nervous system treatment

The central nervous system (CNS) is the brain and spinal cord. If the leukaemia has spread to the CNS, the treatment may include chemotherapy given directly into the spinal fluid, called intrathecal chemotherapy. The drug used in intrathecal chemotherapy is methotrexate or cytarabine. It is usually given during a lumbar puncture^[1].

Supportive care and emotional wellbeing

It is very stressful for patients to be diagnosed with refractory leukaemia. The healthcare team consisting of physicians, nurses, and social workers needs to provide support to the patients and their families and encourage them to have open discussions. Talking to other patients diagnosed with the resistant form of the condition or joining local support groups may also help^[5].

You will have supportive care to help with side effects and symptoms, as well as looking after your physical, emotional and mental health^[19]. Palliative care is crucial to help manage symptoms and side effects of treatment and thus optimize the quality of life of the patient^[5].

It is important to discuss a fresh treatment plan with doctors who have experience dealing with this particular form of AML. Taking part in clinical trials is an option for some patients. Patients are also advised to get a second opinion from another doctor before starting any new treatment^[5].

Your medical team might suggest treatment as part of a clinical trial, if there is one suitable for you. This could let you access treatments that would not otherwise be available. If there is a clinical trial that might be suitable, your medical team should explain what it would involve, and the risks and benefits of taking part. It is your choice whether or not to take part^[19].