Acute promyelocytic leukaemia (APL) treatment and side effects

Patients with APL will begin treatment immediately. This is because of the high risk of severe bleeding if APL is left untreated.

The goal of your treatment will be to achieve remission. There are two levels of remission to be achieved before the disease is cleared:

Morphological remission

A morphological remission is also known as a complete remission (CR). This is achieved when the level of abnormal promyelocytes detected in your bone marrow is less than 5%. This will also be when your blood count has recovered to a normal level.

Molecular remission

A molecular remission is also known as a complete molecular remission (CRm). This is based on the results of your PCR tests (assessed from your bone marrow sample). Achieving a negative PCR means that the test has been unable to detect any trace of the PML/RARA gene – in other words, APL cells cannot be detected by the most sensitive test available.

The PCR test is very sensitive (it can detect one APL cell amongst 10,000 normal cells), so can identify remaining APL cells that aren’t visible under a microscope.

You won’t usually have a PCR test after your first cycle of treatment, because the test would likely be positive at this early stage (which is normal and does not predict your outlook). But you’ll have a PCR test after each further course of therapy.

Most patients (about 95%) achieve CRm by the end of their treatment.

The outlook for people with APL is generally better than for many other forms of blood cancer, although it still depends on a range of factors like age, general fitness, and the type of APL you have. Every person is individual, so your consultant and healthcare team are the best people to ask about your likely outlook (your prognosis).

Most patients with APL have a successful outcome and will achieve molecular remission with treatment. Up to three quarters of all younger, fitter APL patients are treated successfully.

Some rare types of APL are more difficult to treat, and so the outlook may vary. Your prognosis is also likely to be affected if you had a high white blood cell count when you were diagnosed. Your consultant will be able to tell you how these factors affect your outlook.

Talking about your prognosis

You may find it hard to ask or talk about your prognosis. Sometimes those close to you may want to know your prognosis even if you don’t. However, your healthcare team aren’t allowed to give this, or any other information, to anyone – not even family members – without your permission. Try to decide early on who you want to know about your condition, then tell your healthcare team – you can change your mind any time.

First-line therapy

First-line therapy means the treatment plan you’ll have after being diagnosed. If first-line therapy is successful then it’s likely you won’t need any further treatment. The standard first-line therapy regime is made up of four courses of the following drugs.

ATRA

Your treatment is likely to be based around a drug called alltrans retinoic acid (ATRA), which is given as a capsule. ATRA isn’t a chemotherapy drug, but works in combination with chemotherapy. Rather than killing APL cells, it targets the protein formed by the faulty PML/RARA gene. This allows APL cells to mature into normal white cells. You’ll start taking ATRA as soon as your doctor suspects you may have APL. If you begin treatment but your diagnosis then changes after further tests, you’ll stop taking ATRA, but the ATRA you’ve already had won’t do you any harm.

Anthracyclines

Anthracyclines are a group of chemotherapy drugs that join with the DNA in cells and damage the DNA’s structure. They’re especially effective against cells which divide quickly, like cancerous cells. Anthracyclines are given intravenously, meaning they are fed directly into a vein.

You may start on anthracyclines at the same time as ATRA (this is more likely if you have a high white cell count when you’re diagnosed), or you may start a few days afterwards.

Second-line therapy ATO

For those patients who don’t achieve molecular remission by the end of treatment, a drug called arsenic trioxide (ATO) may be effective. ATO works in a similar way to ATRA, by targeting the protein formed by the PML/RARA gene. ATO is given intravenously but a tablet form may also become available.

You may be worried if you’ve heard of arsenic before, as a poison when used in high doses. However, arsenic can also be used safely in medicine, and it is a very effective treatment for APL. ATO isn’t yet widely used as a first-line treatment option. However, ATO is sometimes used in newly diagnosed patients within clinical trials. If there is a clinical trial available, your consultant may offer you the opportunity to consider this. ATO may also be recommended to patients at a higher risk of toxicity, for example those with tAPL who have already received chemotherapy for a previous condition.

Storing your stem cells

A stem cell transplant is what used to be called a bone marrow transplant. It aims to give patients healthy stem cells, which then produce normal blood cells. It isn’t used as part of the standard treatment for APL, but it may be considered as an option for patients who relapse, if they’re in otherwise good general health.

If you’re in molecular remission after your final course of therapy, your healthcare team may suggest harvesting and storing your stem cells. This can be a useful thing to do, so a transplant might be possible if you relapse.

Maintenance therapy

If you have a positive PCR result (if the PML/RARA gene is still detectable) after your third course of treatment with ATRA and anthracyclines, your consultant may recommend extending your treatment over two years. This is known as maintenance therapy. ATRA is normally used for maintenance in combination with chemotherapy drugs called 6-mercaptopurine and methotrexate.

Different people have different responses to their treatment. Even if two patients are having the same treatment, they may have a different experience. You might not get all, or even any, of these side effects – try to bear this in mind when you read about them. You may also like to talk about potential side effects with your healthcare team.

Short-term side effects from chemotherapy

You may experience some short-term side effects from your chemotherapy treatment. These may include the following:

• an achy feeling
• constipation
• diarrhoea
• extreme tiredness
• infections
• rashes
• sore mouth/mouth ulcers
• nausea and vomiting.

You’re unlikely to have all of these. If you have side effects, do tell your healthcare team as they may be able to help with them – there are medicines you can take to help with nausea and vomiting, for instance.

Differentiation syndrome

Some patients treated with ATRA or ATO will experience a condition called differentiation syndrome, also known as retinoic acid syndrome or RA syndrome. This can happen when ATRA or ATO cause the APL cells to mature into white blood cells. This is an important part of treating the disease, but when large numbers of white blood cells are present it can cause problems. It’s most likely to happen during the first three weeks of treatment of newly diagnosed or relapsed APL.

The signs and symptoms include a cough, difficulty breathing, fever, weight gain, fluid in the tissues and fluid in the membranes around the heart and lungs, which can cause a shadowing of the lungs on x-rays.

Differentiation syndrome can usually be treated with steroids. Your doctor may also recommend you stop taking ATRA/ATO for a few days.

If you have a high white blood cell count when you’re diagnosed, you may be at higher risk of differentiation syndrome. Your doctor may suggest you take steroids as a precaution to try and stop it happening.

Long-term side effects from chemotherapy

The long term effects of chemotherapy depend on which drugs you take, the intensity of your treatment and, in some cases, the total amount of the drug you take. Your specialist will discuss these potential side effects with you before you start your treatment.

Anthracyclines can cause heart damage, more often in older patients. The level of damage caused to the heart, and the likelihood of you developing this at all, will depend on the amount of anthracyclines you need to take. If you relapse and need more treatment, your healthcare team will consider what will be the most effective treatment for you, with the least possible side effects.

> For more information about side effects download or order our booklet: Chemotherapy

Infertility

You may be worried about the effect of your treatment on your fertility. It’s a concern that many patients have, and one that also impacts on their partners and families too. If you’re having treatment for APL at an age when you’re thinking about having children or more children, you might want to discuss your options for protecting your fertility with your doctor.

Some chemotherapy drugs may have a temporary effect on fertility.

For men, chemotherapy drugs might affect sperm production and cause infertility. However, recent clinical studies have shown that most patients get normal sperm function back once they’ve finished chemotherapy.

For women, chemotherapy without radiotherapy is less likely to lead to infertility.

It’s very important that female patients don’t become pregnant while taking ATRA or ATO. If you’re sexually active while on treatment it’s recommended that you use at least two reliable forms of contraception.

Permanent infertility is more common in patients who’ve had a stem cell transplant after high doses of chemotherapy and/or whole body irradiation, which are less common treatment options for APL.

It’s natural to worry about the effects of treatment on any children you may have after your treatment. Lots of evidence from clinical studies has shown that a parent's cancer treatment doesn’t lead to an increased risk of cancer or other health problems in their children.

The aim of follow-up is to look out for signs of relapse and treatment complications. These appointments are really important so do make sure you get to them.

For the first year after your treatment, you’ll normally have a check-up every one to two months. After one year, your check-ups will get less and less frequent, until they’re given every year at five years and onwards. Your follow-up will also include regular testing of your bone marrow using a bone marrow aspirate, like you had when you were diagnosed.

Your doctors will monitor for relapse using the PCR test throughout your follow up. The test means they’ll be able to detect a relapse early in most cases.

Relapse testing is important for all patients, but especially if you had a high white cell count when you were diagnosed, as your risk of relapse is higher.

Between 10 and 25% of patients who achieve a morphological remission will go on to experience a relapse. If you do relapse, there are a number of treatment options available. Your healthcare team will discuss the best way forward with you.

Treatment of patients at high risk of relapse

If your PCR test at the end of your final course of therapy shows any APL cells left in your bone marrow, you’ll need further treatment to prevent a relapse. This will usually be with the drug ATO.

The aim of this treatment is to achieve molecular remission, meaning that no APL cells are visible, even in a PCR test.

Types of relapse

Haematological relapse

If APL cells can be seen under a microscope at the time a relapse is identified, this is called a haematological relapse. Arsenic trioxide (ATO) is the standard treatment for relapsed APL.

Molecular relapse

When no APL cells are visible under a microscope but the more sensitive PCR test does reveal APL cells, this is known as a molecular relapse. If this happens, you’ll usually start by taking ATRA before additional treatment such as ATO is given.

A second PCR test will be done on your bone marrow to confirm the result of molecular relapse.

Extramedullary relapse

Although relapse usually occurs in the bone marrow, about 10% of all relapses are in places outside the bone marrow. This is known as an extramedullary (EM) relapse. Most EM relapses are in the central nervous system (CNS) – which involves the brain and spinal cord. It mostly happens in patients who had a high white cell count when they were diagnosed.

To test for CNS disease, your doctors will perform a brain scan and assess the fluid that surrounds the brain and spinal cord for APL cells. The procedure for this is called a lumbar puncture test. APL in the CNS can be treated by chemotherapy injections and radiotherapy.

Other treatment options for relapse

Gemtuzumab ozogamicin

If your treatment for a relapse with ATO isn’t successful and you don’t achieve molecular remission, you may be offered a drug called gemtuzumab ozogamicin (also known as Mylotarg). This targets a protein that’s present on APL cells.

Chemotherapy

Chemotherapy may also be added to your treatment. Your consultant will discuss this with you if this is the case.

Stem cell transplant

You might also have the option of a stem cell transplant as part of your relapse treatment. This is offered if you’re in good general health and the other types of treatment haven’t worked to achieve molecular remission.

A stem cell transplant may also be used after successful relapse treatment, to prevent the APL from returning a second time.

If you had your stem cells harvested earlier when in molecular remission, you may be offered a transplant using these cells. This is called an autologous transplant.

A transplant using stem cells from a matched donor (an allogeneic transplant) can be effective for some patients. However it’s a high risk procedure and because of this your doctors may recommend an autologous transplant, even if a donor is available.

A ‘mini-transplant’ might also be an option. This is similar to a donor transplant but the treatment you have beforehand is less intensive.

> For more information on stem cell transplants download or order our booklet: Seven steps: blood and bone marrow transplantation