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Home , Bone marrow suppression, FLAG (chemotherapy)

FLAG-Ida for Acute Myeloid Leukaemia (AML)

A Guide for Patients Introduction

FLAG-Ida is a combination regimen made up of fludarabine, high dose cytarabine (Ara-C0), and granulocyte-colony stimulating factor (G-CSF) used in the treatment of acute myeloid leukaemia (AML).

This booklet has been compiled by Saloua Najjam, PhD (Haematology) and peer reviewed by one of our medical professionals, Nurse Advisor Fiona Heath. We are also grateful to Julie Quigley, AML patient reviewer, for her valuable contribution. This booklet has then been updated by our Patient Information Writer, Isabelle Leach.

If you would like any information on the sources used for this booklet, please email [email protected] for a list of references.

Version 2 Printed: 01/2020 2 www.leukaemiacare.org.uk Review date: 01/2022 In this booklet

Introduction 2 In this booklet 3 About Leukaemia Care 4 What is FLAG-Ida? 6 Who receives FLAG-Ida? 10 How is FLAG-Ida administered? 11 What are the side effects of FLAG-Ida? 13 What happens if FLAG-Ida doesn’t work? 16 Glossary 17 Useful contacts and further support 19

Helpline freephone 08088 010 444 3 About Leukaemia Care

Leukaemia Care is a national charity dedicated to ensuring that people affected by blood cancer have access to the right information, advice and support.

Our services has been affected by a blood cancer. A full list of titles – both Helpline disease specific and general Our helpline is available 8:30am information titles – can be – 5:00pm Monday - Friday and found on our website at www. 7:00pm – 10:00pm on Thursdays leukaemiacare.org.uk/support- and Fridays. If you need someone and-information/help-and- to talk to, call 08088 010 444. resources/information-booklets/

Alternatively, you can send Support Groups a message via WhatsApp on Our nationwide support groups 07500068065 on weekdays are a chance to meet and talk 9:00am – 5:00pm. to other people who are going Nurse service through a similar experience. For more information about a We have two trained nurses on support group local to your area, hand to answer your questions go to www.leukaemiacare.org. and offer advice and support, uk/support-and-information/ whether it be through emailing support-for-you/find-a-support- [email protected] or group/ over the phone on 08088 010 444. Buddy Support Patient Information Booklets We offer one-to-one phone We have a number of patient support with volunteers who have information booklets like had blood cancer themselves this available to anyone who or been affected by it in some

4 www.leukaemiacare.org.uk way. You can speak to someone Website who knows what you are going You can access up-to-date through. For more information information on our website, on how to get a buddy call www.leukaemiacare.org.uk. 08088 010 444 or email [email protected] Campaigning and Advocacy Online Forum Leukaemia Care is involved in campaigning for patient well- Our online forum, being, NHS funding and drug www.healthunlocked.com/ and treatment availability. If you leukaemia-care, is a place would like an update on any of for people to ask questions the work we are currently doing or anonymously or to join in the want to know how to get involved, discussion with other people in a email advocacy@leukaemiacare. similar situation. org.uk Patient and carer conferences Patient magazine Our nationwide conferences Our magazine includes provide an opportunity to inspirational patient and carer ask questions and listen to stories as well as informative patient speakers and medical articles by medical professionals: professionals who can provide www.leukaemiacare.org.uk/ valuable information and support. communication-preferences/

Helpline freephone 08088 010 444 5 What is FLAG-Ida?

FLAG-Ida is the abbreviation for Cytarabine a combination of drugs which has shown to be effective for Cytarabine (also called cytosine the treatment of AML. FLAG- arabinidose or Ara-C) is also an Ida consists of fludarabine, chemotherapy cytarabine (Ara-C), granulocyte- drug that has been used for the colony stimulating factor (G-CSF) treatment of AML for over 40 and idarubicin. years. Cytarabine is used in combination Fludarabine with other for Fludarabine is a type of the treatment of AML, acute chemotherapy drug called an lymphoblastic leukaemia antimetabolite. and crises in chronic myeloid interfere with the synthesis leukaemia. of DNA, and therefore prevent the growth or reproduction of Cytarabine is available as leukaemia cells. a concentrated solution for injection or infusion. Fludarabine is indicated for the treatment of adult patients with Idarubicin chronic lymphocytic leukaemia Idarubicin is a drug that belongs (CLL) in combination with to a group of anti-cancer and rituximab drugs called . (FCR), but when used as part of These drugs were originally the FLAG-Ida combination, it has used as , but it was been very useful for the treatment subsequently found that they of AML. were effective anti-cancer drugs. Fludarabine is available as Anthracyclines work by damaging a concentrated solution for DNA of the leukaemia cells. injection or infusion, or as a Idarubicin is indicated for the tablet. treatment of patients with AML and relapsed/refractory acute

6 www.leukaemiacare.org.uk lymphoblastic leukaemia (ALL). treatments.

Idarubicin is available as a freeze- G-CSFs are available as solutions dried powder to be made into a for injection or infusion. It solution for injection or infusion, is included in the FLAG-Ida or as a tablet, if an injection or regimen from the day before the infusion is not possible. chemotherapy drugs start to try to bring the leukaemic cells G-CSF into cycle and increase their G-CSF is a growth factor which sensitivity to the chemotherapy stimulates the to agents. produce granulocyte white blood cells, mainly the neutrophils. FLAG-Ida Granulocytes (white blood cells The aim of treatment for AML is that are characterised by small to cure the majority of patients granules in their cells) include who are able to tolerate intensive the neutrophils, eosinophils and chemotherapy, as well as improve basophils. Neutrophils protect supportive care and availability of against bacterial and allogeneic stem cell transplants. inflammation. Eosinophils protect FLAG-Ida is a chemotherapy against parasites and allergens, regimen widely used in patients and basophils create the with relapsed or refractory AML. inflammatory reactions during an It is often used in patients with immune response. refractory or relapsed AML who are G-CSFs are indicated for the awaiting an allogeneic stem cell improvement of transplant. (a decrease in the number FLAG-Ida has also been shown to of neutrophils) caused by achieve complete remission in chemotherapy. G-CSFs are not newly diagnosed patients. One cancer treatments, but supportive course of FLAG-Ida resulted in care medicines for patients more remissions and reduced with bone marrow suppression relapse compared with the secondary to cancer and its

Helpline freephone 08088 010 444 7 What is FLAG-Ida? (cont.)

standard care treatment for AML (e.g. FLT3-ITD in the absence of cytarabine with daunorubicin of an NPM1 mutation, p53 in younger patients with AML. mutations, ASXL1 or RUNX1 Daunorubicin is an mutations) drug like idarubicin. Patients Patients with secondary treated with FLAG-Ida require • AML (following previous more supportive care than haematological conditions patients receiving daunorubicin like MDS, MPNs) or therapy- and cytarabine. The duration of related AML following previous neutropenia is slightly longer, chemotherapy. they need more transfusions and antibiotics, on average spend Many high-risk patients now slightly longer in hospital, and receive CPX-351 (Vyxeos) as their they experienced bone marrow initial therapy. suppression which can prevent some of them completing the full course of treatment.

The FLAG-Ida regimen is given for two cycles and includes fludarabine for four days, cytarabine for four days, idarubicin for three days and G-CSF for six days. Sometimes idarubicin is omitted from the second cycle.

High-risk AML includes a number of groups of patients: • Those with high-risk cytogenetic abnormalities, or those with high-risk molecular features

8 www.leukaemiacare.org.uk Helpline freephone 08088 010 444 9 Who receives FLAG-Ida?

Patients with AML who may benefit from the FLAG-Ida If you wish to have further combination therapy are the information on AML or APL, following: please view our collection of patient information • Patients with relapsed or booklets that are available refractory AML, who may or may on our website at www. not be awaiting an allogeneic leukaemiacare.org.uk stem cell transplant • Newly diagnosed patients with AML as an induction of remission (particularly those with high-risk disease features) • Patients whose induction therapy with cytarabine and daunorubicin or daunorubicin with cytarabine and etoposide has not worked (refractory AML)

Patients with acute promyelocytic leukaemia (APL), which is a subtype of AML, should not be treated with FLAG-Ida as the combination of differentiating agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) achieves excellent cure rates of 85% (for high-risk patients) to over 90% (for low- to intermediate- risk patients) in these patients.

10 www.leukaemiacare.org.uk How is FLAG-Ida administered?

Before starting FLAG-Ida to your partner or unborn baby. treatment, the following clinical You will then need to read and assessments will be carried out: sign a consent form regarding • Measurement of your weight the receipt of verbal and written and height. information in relation to your disease, treatment and potential Full blood count and urea and • side effects. electrolyte levels as a measure of kidney function. These tests For part of your induction therapy, will be performed before each you will be treated in the hospital treatment cycle. for a period of around four weeks, but this may vary from person to A pregnancy test will be carried • person. Your stay in the hospital out on all female patients of is separated by a short period of child bearing age two weeks stay at home, to rest between the before starting treatment. two given courses of FLAG-Ida. Electrocardiograms (ECGs), • The two cycles of FLAG-Ida include: echocardiograms (ECHOs) or multiple-gated acquisition • The injection of G-CSF is given (MUGA) scans for patients under the skin in the abdomen with a cardiac history, elderly or leg for seven consecutive patients or those with a history days (days one to seven). of heart disease. • Fludarabine given via an Details and facilities available infusion over 30 minutes once for managing any side effects or a day for five consecutive days complications will be explained (days two to six). to you, and patients should be Cytarabine given via an infusion informed on the importance • over four hours once a day (four of using adequate barrier hours after the fludarabine) for contraception as the drugs in the five days (days two to six). FLAG-Ida regimen can be harmful

Helpline freephone 08088 010 444 11 How is FLAG-Ida administered? (cont.)

• Idarubicin given via an infusion over one hour, once a day for three days. Sometimes idarubicin is omitted from the second cycle.

The doses of the individual chemotherapies in the FLAG-Ida regimen will be adjusted in line with your medical history and the results of your pre-treatment assessments.

The levels of creatinine and bilirubin in your blood during treatment will indicate any kidney or liver impairment, respectively. Your doctor will modify the doses within FLAG-Ida accordingly. If there are any signs of heart damage or impairment, idarubicin will be stopped.

12 www.leukaemiacare.org.uk What are the side effects of FLAG-Ida?

The side effects of FLAG-Ida may severity of this varies from be caused by any of the drugs in person to person. Anti-sickness the regimen. medication will be given along with your chemotherapy to Common side effects prevent this. • Bruising or bleeding – This • Eye irritation – This is a known treatment can reduce the side effect of cytarabine. You will production of which be given eye drops to try and help the blood clot. You may prevent this. need transfusions. • Hair loss – Your hair will • Anaemia (low number of red gradually fall out 10 to 14 days blood cells) – You may become following your first course of anaemic, which can make you treatment. The timescale varies feel tired and breathless. You from person to person. This is a will have a routine blood test temporary side effect and your every day you are in hospital to hair will grow back when your monitor your full blood count treatment is completed. and you may require blood transfusions. • Discolouration of urine – Idarubicin, because of its red • Increased risk of serious colour, may discolour your urine – You are vulnerable to red or pink for the first few infection while you are having times following treatment. chemotherapy. Minor infections can become life-threatening in a • Fatigue – You may feel tired and matter of hours if left untreated. lacking in energy, especially Symptoms of infections include when your blood counts are low. fever, shivering, sweats, sore throat and diarrhoea. Uncommon side effects G-CSF can sometimes cause • Nausea and vomiting - The • pain or an aching sensation in

Helpline freephone 08088 010 444 13 What are the side effects of FLAG-Ida? (cont.)

your bones. Rare side effects • Cytarabine can sometimes • Irregular heartbeat – cause a set of symptoms Occasionally this can happen during its infusion known as as a result of the idarubicin. cytarabine syndrome. These It is quite rare and usually symptoms include fever, a rash, reversible. aching in your muscles and bones, and pain in the chest. • Skin changes – Sometimes These symptoms usually occur after having FLAG-Ida, your skin six to 12 hours following the may appear darker in colour infusion and will stop once or lightly tanned, especially the infusion of cytarabine is around the joints. This is called finished. hyperpigmentation. Your skin will return to normal after the • Diarrhoea – If this becomes a treatment has been completed. problem anti-diarrhoea tablets can be prescribed. • Protecting your partner and contraception – It is • Mucositis (sore mouth) – Your recommended that you or mouth may become sore or dry your partner use a condom and you may develop mouth during sexual intercourse while ulcers. Drinking plenty of you are having the course of fluids and cleaning your teeth chemotherapy. Chemotherapy regularly and gently with a soft is dangerous to unborn babies toothbrush can help reduce and this will also protect you the risk of this happening. and your partner from any Occasionally during treatment, chemotherapy drugs that may you may experience a strange be present in semen and in the metallic or bitter taste. A strong vagina. flavoured sweet or mint may help with this. • Fertility – This chemotherapy may affect your ability to have

14 www.leukaemiacare.org.uk children. You should discuss treatment with FLAG-Ida. this with your doctor or nurse The addition of idarubicin to the before you start treatment. FLAG schedule will be decided Very rare side effects carefully by your consultant as this drug is contra-indicated in • Serious allergic reactions. the following patients: • Minor ulceration of the gastric • Patients with severe myocardial mucosa (the mucus layer of the insufficiency, who have had a stomach). recent heart attack (myocardial • Hand-foot syndrome (redness, infarction). swelling, and pain on the palms • Patients with severe arrhythmia of the hands and/or soles of the (a condition in which the heart feet). beats with an irregular or • Blockage of a blood vessel by abnormal rhythm). a blood clot that has become • Patients who have unstable moved from another side in the angina (a condition marked by circulation (thromboembolism). severe pain in the chest, often • Transfusion-associated graft- spreading to the shoulders, versus-host-disease (TA-GvHD) arms, and neck). – Fludarabine weakens your • Patients who suffer from , so when you cardiomyopathy, which is a have a transfusion of blood condition in which the heart products you are at a higher muscle is damaged. risk of developing TA-GvHD. This extremely rare condition • Patients with a previous can cause a severe rejection treatment history of cumulative reaction. It is almost fully doses of idarubicin or other prevented by gamma irradiation anthracyclines. of any of the blood products you are given once you have had

Helpline freephone 08088 010 444 15 What happens if FLAG-Ida doesn’t work?

Overall, following the outcome of your treatment with FLAG- Leukaemia Care offers Ida, your consultant is the best nationwide support groups person to discuss your options for people affected by a with and to decide on the next diagnosis of a blood or step to take. Your clinician will be lymphatic cancer. Visit able to discuss options with you www.leukaemiacare.org. that might include alternative uk, or call 08088 010 444, chemotherapy combinations or to find out more and to find recruitment to clinical trials of a group near you. novel therapeutic options.

16 www.leukaemiacare.org.uk Glossary

Acute Lymphoblastic Bone Marrow Leukaemia (ALL) The soft blood-forming tissue A leukaemia in which that fills the cavities of bones lymphocytes start multiplying and contains fat, immature and uncontrollably in the bone marrow mature blood cells, including resulting in high numbers of white blood cells, red blood cells abnormal, immature lymphocytes and platelets. called blasts. Lymphocytes are a type of involved in Chemotherapy the immune response. Drugs that work in different ways to stop the growth of cancer cells, Acute Myeloid Leukaemia (AML) either by killing the cells or by A rapid and aggressive cancer stopping them from dividing. of the myeloid cells in the bone marrow. Chromosome X-shaped, thread-like structures Acute Promyelocytic which carry the genes, and are Leukaemia (APL) located in the nuclei of every A rare sub-type of AML in which cell in the body. There are 46 there is an increased production chromosome (23 pairs) in of immature, abnormal white humans. blood cells called promyelocytes Creatinine in the bone marrow. The breakdown product of Antimetabolite creatine that results from the A drug that interferes with normal wear and tear of muscles the enzymes necessary for in the body. DNA synthesis, and therefore Electrolytes preventing growth or reproduction of cells. Salts and minerals in the blood that help conduct electrical Bilirubin impulses in the body. They include The breakdown product of red sodium, potassium, chloride and blood cells. bicarbonate, among others.

Helpline freephone 08088 010 444 17 Glossary (cont.)

FLT3-ITD (FMS-like tyrosine Neutrophils kinase 3-Internal tandem White blood cells involved in duplication) mutation fighting inflammation and The mutation in a gene called infection, specifically bacterial FLT3 due to internal tandem infections. duplication of the gene. FLT3 Relapse is mutated in about a third of patients with AML. Patients with A relapse occurs when a patient FLT3-ITD mutations have lower initially responds to treatment, cure rates due to an increased but the leukaemia then comes risk relapse. back at a later point. This is also sometimes called a recurrence. Full Blood Count Remission A full blood count is performed on a blood sample using automated ‘Complete Remission’ is said to equipment to provide the have occurred when the blood concentration of haemoglobin in cell counts have returned to the blood, measures of the red cell normal and there are less than 5% components, the white cell count, abnormal, immature leukaemia including the different types of cells still present in the bone white cells, and the platelet count. marrow. Induction TP53 (tumour protein 53) The treatment phase intended to Mutation kill the majority of the leukaemia The TP53 gene is located on cells in the blood and bone chromosome 17. The TP53 protein marrow, and to restore normal is responsible for preventing blood cell production, i.e. to cells from over-multiplying and induce a disease remission. switching on the destruction of cells with damaged DNA. The Intravenous Infusion mutation in this gene is the most The administration of fluids into common mutation associated a vein using a steel needle or with human cancers. plastic catheter.

18 www.leukaemiacare.org.uk Useful contacts and further support

There are a number of helpful Bloodwise sources to support you during Bloodwise is the leading charity your diagnosis, treatment and into the research of blood cancers. beyond, including: They offer support to patients, • Your haematologist and their family and friends through healthcare team patient services. • Your family and friends 020 7504 2200 • Your psychologist (ask your www.bloodwise.org.uk haematologist or CNS for a Cancer Research UK referral) Cancer Research UK is a leading Reliable online sources, • charity dedicated to cancer such as Leukaemia Care research. Charitable organisations • 0808 800 4040 There are a number of www.cancerresearchuk.org organisations, including ourselves, who provide expert Macmillan advice and information. Macmillan provides free practical, Leukaemia Care medical and financial support for people facing cancer. We are a charity dedicated to 0808 808 0000 supporting anyone affected by www.macmillan.org.uk the diagnosis of any blood cancer. We provide emotional support Maggie’s Centres through a range of support Maggie’s offers free practical, services including a helpline, emotional and social support patient and carer conferences, to people with cancer and their support group, informative families and friends. website, one-to-one buddy service and high-quality patient 0300 123 1801 information. We also have a nurse www.maggiescentres.org on our help line for any medical Citizens Advice Bureau (CAB) queries relating to your diagnosis. Offers advice on benefits and Helpline: 08088 010 444 financial assistance. www.leukaemiacare.org.uk [email protected] 08444 111 444 www.adviceguide.org.uk

Helpline freephone 08088 010 444 19 Leukaemia Care is a national charity dedicated to providing information, advice and support to anyone affected by a blood cancer.

Around 34,000 new cases of blood cancer are diagnosed in the UK each year. We are here to support you, whether you’re a patient, carer or family member.

Want to talk?

Helpline: 08088 010 444 (free from landlines and all major mobile networks) Office Line: 01905 755977 www.leukaemiacare.org.uk [email protected]

Leukaemia Care, One Birch Court, Blackpole East, Worcester, WR3 8SG

Leukaemia Care is registered as a charity in England and Wales (no.1183890) and Scotland (no. SCO49802). Company number: 11911752 (England and Wales). Registered office address: One Birch Court, Blackpole East, Worcester, WR3 8SG