Relapse in Acute Lymphoblastic Leukaemia (ALL)

A Guide for Patients Introduction

A relapse is the return of leukaemia after treatment. Specifically, this booklet is about a relapse in acute lymphoblastic leukaemia (ALL).

The booklet was written by our Patient Information Writer, Isabelle Leach, and peer reviewed by Dr. Richard Kaczmarski at The Hillington Hospital NHS Foundation Trust, Dr Mark Mansour at University College of London Cancer Institute and Dr David O’Connor at GOSH. We are also grateful to our reviewer, Kerri Baker, whose son had a relapse in ALL, for their contribution.

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

Version 1 Printed: 01/2019 2 www.leukaemiacare.org.uk Review date: 01/2021 In this booklet

Introduction 2

In this booklet 3

About Leukaemia Care 4

What is Acute Lymphoblastic Leukaemia? 6

What is a relapse? 8

Symptoms and diagnosis of relapsed ALL 12

How is relapsed ALL treated? 14

Glossary 20

Useful contacts and further support 23

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.

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Helpline freephone 08088 010 444 5 What is Acute Lymphoblastic Leukaemia?

In acute lymphoblastic leukaemia ••Five-year survival is (ALL), high numbers of abnormal, approximately 90% in children, immature lymphocytes called but only 30% to 40% in adults blasts start over-multiplying in and elderly patients. the bone marrow. Lymphocytes are white blood cells involved in In children with ALL: the immune response. There are ••80% to 85% of ALL consists two types of lymphocytes: of early B-cells (also called precursor B-cell) 1. B-cells (formed in the bone marrow) which produce ••15% are early T-cells antibodies that seek out and Approximately 2% are mature immobilise bacteria, viruses, •• B-cells and toxins which invade the body. In adults with ALL: 2. T-cells (formed in the thymus ••75% of cases are early B-cells gland, behind the sternum) 25% are malignant early T-cells which destroy the invading •• organisms that have been Prognostic risk factors tagged by the B-cells as well as any cells that have become Prognostic risk factors at initial cancerous. presentation, which can also be used to inidicate a poor outcome ALL has different rates of or the chances of a relapse occurrence, survival and type of occurring, include: lymphocytes involved in children and adults: ••Age at diagnosis: younger than 6 months and older than 60 ••Approximately 50% of patients years with ALL are children under 15 years of age (with a peak from ••Male sex, possibly because of two to five years of age), and the impact of a major relapse the remaining 15% of ALL cases site being in the testicles are adults, mainly aged over 50 ••High white blood cell count of years.

6 www.leukaemiacare.org.uk greater than 300,000 white blood cells x 106 cells/L ••T-cell lymphocyte ALL rather than B-cell lymphocyte ALL ••Spread of ALL to the central nervous system (CNS)

Certain abnormal gene rearrangements can also act as prognostic risk factors. These include: ••t(9;22) BCR-ABL1 (Philadelphia chromosome) ••MLL (KMT2A) translocations ••t(17;19) TCF3-HLF ••Near haploidy (24-30 chromosomes). Haploidy is having only half of the normal number of 46 chromosomes ••Low hypodiploidy (31–39 chromosomes). Hypodiploidy is having less than the normal number of 46 chromosomes

Helpline freephone 08088 010 444 7 What is a relapse?

What is a relapse? in their bone marrow after treatment. This is called refractory Relapse in ALL is the return of ALL. ALL in patients who have already undergone treatment and reached Between 10% and 20% of patients, complete remission. who have achieved complete remission after initial treatment For complete remission to have for ALL, will have a relapse. In occurred, the following conditions children, the relapse rate is near will have been met: to 10%, while in adults relapse rate ••Blood cell counts returned to is closer to 50%. Relapse of ALL normal generally occurs within two years of initial treatment, although ••Less than 5% of blasts it may occur several months to (abnormal, immature, early years after the initial remission. lymphocytes) are still present in the bone marrow Why does relapse ••There is no leukaemia present happen? elsewhere in the body Patients with ALL are known to have a number of characteristics When a relapse occurs, as with that make them more likely to newly-diagnosed ALL, the blasts, relapse. Patients with a likelihood which begin in the bone marrow, or risk that they will have a start over-multiplying again, relapse after treatment can be reaching high levels beyond subdivided into well-defined levels considered appropriate for risk groups according to these remission. This is also called a characteristics. recurrence. By way of an example, there is a While a large number of patients well-established risk stratification go into remission after induction for ALL patients, which is used by therapy, there are subsets of many doctors, shown below. This patients who do not at all, and risk stratification is for children still have numerous blast cells since the majority of patients with

8 www.leukaemiacare.org.uk ALL are children. Chromosomes are thread-like structures which carry the genes National Cancer and are located in the nuclei Institute/Rome criteria of every cell. Genes are made for children up of DNA (deoxyribonucleic acid) which stores the genetic The National Cancer Institute/ information required to make Rome criteria uses only patients’ human proteins. ages and white blood cell counts to determine their risk, and The presence of abnormal gene predict relapse and outcome. rearrangements alone cannot predict a relapse rate in patients, Standard risk - Both of the but the relationship between following criteria must be genetic rearrangements and the present: prognosis of the first occurrence ••White blood cell count less than of ALL can. 50 x 109 cells/L How often does relapse ••Age of patient between one and occur? nine years Despite the fact that around 85% High risk - Both of the following of cases of ALL occur in children, criteria must be present: its presence in the remaining ••White blood cell count greater 15% of adults who get ALL carries than 50 x 109 cells/L a much more serious prognosis than the children. ••Age of patient younger than one year or older than nine years In children, although complete remission occurs in 97 to 99% of Since this risk classification patients following initial multi- was established, numerous agent chemotherapy treatment, other risks factors for relapse between 15 and 20% will have a have been found, none more relapse. so than the implications of faulty chromosomes and genes. In adults, despite complete

Helpline freephone 08088 010 444 9 What is a relapse? (cont.)

remission rates of between 78% and 93%, relapse will occur in 60- 70% of patients.

In addition to different rates of relapse for ALL patients according to their age at diagnosis, other prognostic factors at initial presentation can also indicate those patients where relapse occurs more often.

Although not having any of the prognostic risk factors at initial presentation predicts less chance of relapse and a better outcome, there is always a risk of relapse irrespective of a patient’s age or prognostic factors.

10 www.leukaemiacare.org.uk Helpline freephone 08088 010 444 11 Symptoms and diagnosis of relapsed ALL

What are the platelets. In a relapse, ALL patients have lower-than-expected red symptoms of relapsed blood cells and platelets. ALL? A peripheral blood smear The symptoms of relapsed ALL are the same as those for newly A sample of blood is viewed under diagnosed ALL, and include: a microscope to count different circulating blood cells and to see ••Anaemia whether the cells look normal. In ••Bruising or petechiae (small red relapsed ALL patients, there are spots on the skin) too many blast cells. ••Fever Bone marrow aspiration and biopsy Recurrent infections •• The aspiration procedure removes ••Abdominal pain a liquid marrow sample and the biopsy removes a small amount ••Bone and joint pain of bone filled with marrow. ••Swollen lymph nodes (showing Medication is given to numb the up as lumps and bumps on your area, or a general anaesthetic is neck, armpits and groin) performed, to remove a sample from the hip bone. The following ••Dyspnoea (difficulty in can be examined: breathing) ••Percentage of ALL cells are in How is relapsed ALL your bone marrow diagnosed? ••Any abnormalities of the ALL To make a diagnosis of relapsed cells ALL, your doctor will carry out the Immunophenotyping following tests: This procedure identifies the Full blood count (FBC) types of proteins on the surface of This will show the number of red the cell to find out if the ALL cells blood cells, white blood cells and are B-cells or T-cells.

12 www.leukaemiacare.org.uk Lumbar puncture This will determine if the ALL cells are in your CNS. Chromosomal analysis (also called cytogenetic analysis) The blood smear sample can also be used to identify certain changes in the number and size of chromosomes within cells that might have led to the relapse. Other tests and scans X-rays are used to monitor the presence of ALL in any organs.

Helpline freephone 08088 010 444 13 How is relapsed ALL treated?

Patients with relapsed ALL remain another complete remission. curable despite the failure of the The treatment of relapsed ALL is initial course of treatment. The normally more intensive than for treatment strategies for adult newly diagnosed ALL. Treatment patients with ALL are similar to outcome depends on the time of those for children with ALL. the patient’s relapse and the type of ALL: The mainstay of the treatment for relapse ALL is chemotherapy, ••For patients who relapse often given with steroids to during, or just after finishing improve the effectiveness. If chemotherapy, another course required, novel target therapy of chemotherapy is unlikely to drugs which attack specific achieve a cure. An ASCT in the components of the leukaemia second remission period is the cells can be given. High-risk only way to cure these patients patients are frequently offered an with ALL, and should be the allogeneic stem cell transplant main focus whenever possible. (ASCT) because the likelihood of a For patients who relapse six cure with chemotherapy alone is •• months or longer after finishing very low. treatment, many patients can Chemotherapy achieve a second remission with therapy similar to that Chemotherapy for ALL used in initial treatment. normally consists of induction, consolidation, and long-term ••For patients with B-cell ALL maintenance therapy, with CNS with a late first bone marrow prophylaxis treatment to prevent relapse and low levels of MRD, blast cells entering the brain or chemotherapy can achieve a spinal cord, often given during the positive outcome. In addition, first year of treatment. the dual specific antibody, blinatumumab, is known to After a first relapse, patients inactivate the T-cell immune should receive re-induction response against B-cells and therapy to try and achieve

14 www.leukaemiacare.org.uk directly activate T-cells against prognosis for both children and the ALL blasts. Blinatumumab is adults. It only occurs in 3% to recommended by the National 5% of patients with ALL, but less Institute for Health and Care than 40% of them are cured with Excellence (NICE) as an option intensive chemotherapy. for treating Philadelphia A young person who is chromosome-negative relapsed Philadelphia chromosome- or refractory B-cell precursor positive will be a candidate for ALL in adults. A recent study of an ASCT in the first remission. 113 adults with B-cell precursor Patients who relapse but achieve ALL in complete haematological a second complete remission remission showed that may also benefit from an blinatumumab achieved a ASCT. However, the success complete MRD response in 78% of tyrosine kinase inhibitors of patients. However, an ASCT, in chronic myeloid leukaemia particularly for those patients (CML) has encouraged their use with unfavourable genetic in Philadelphia chromosome- factors and/or who are MRD- positive ALL patients. The positive, offers a significant tyrosine kinase inhibitor, benefit. imatinib, has achieved complete ••For patients with T-cell remission rates of 90%-100% for ALL, intensive multi-agent patients who have Philadelphia chemotherapy can achieve good chromosome-positive ALL with outcomes. relatively low toxicity. However, the combination of a tyrosine Discovery of abnormal gene kinase inhibitor with standard rearrangements in patients chemotherapy has led to a longer with ALL will also influence survival in both adults and the choice of treatment. The children. Philadelphia chromosome (BCR- ABL) is the most common genetic Relapses can result from a abnormality associated with lack of response to standard adult ALL and has a very poor chemotherapy agents. In patients

Helpline freephone 08088 010 444 15 How is relapsed ALL treated? (cont.)

with refractory ALL, or patients Clinical trials of CAR T-cell therapy who have had several relapses, for relapsed or refractory B-cell multidrug treatment is often cancers, such as B-cell leukaemia used with the aim of eliminating and lymphoma, and several solid blast cells and targeting therapy- tumors, have shown promising resistant cells that could cause results. The anti-CD19 CAR T-cell further episodes of relapse. therapy has achieved remission in up to 90% of patients with Introduction of new treatments B-cell ALL. CD19 is a B-cell receptor from trials for high-risk patients associated protein present on is an option for improving the surface of B-cells. However, outcome. Other possibilities relapse after CAR T-cell therapy is which can also be explored still a problem, often because the include the following: ALL cells lose expression of CD19. Ground-breaking combinations •• The anti-CD19 agent of chemotherapy drugs tisagenlecleucel (Kymriah) is ••Antibodies directed against the the first CAR T-cell therapy to be leukaemia approved in the United States for the treatment of patients up to 25 ••Drugs that stimulate the body’s years of age with B-cell ALL that immune system to attack the is refractory or in second or later leukaemia relapse. In Europe, this anti-CD19 Chimeric Antigen Receptor CAR T-cell drug has been approved (CAR) T-cell therapy: by the European Medicines Agency and NICE. This new cancer treatment works by removing the patient’s Chemotherapy for T-cell ALL, own immune cells, genetically paying special attention to the modifying them to recognise the patient’s responses to previous tumour cells, and then re-infusing treatments, has also resulted in them back into the patient so they good survival rates. Patients with can target the cancer cells. mature T-cell ALL have a better outcome than those with early

16 www.leukaemiacare.org.uk T-cell ALL. Careful selection of SCT for ALL patients is important to achieve A major challenge in the future the best outcomes. Human treatment of ALL will be to devise leukocyte antigen (HLA)-matched less toxic regimens for patients sibling donors are recognised as with low-risk disease and high the best option, but this is only cure potential, with the ultimate available for 30% of patients. goal of improving their quality of Alternative sources of stem cells life. for the remaining 70% of patients Allogeneic stem cell include matched unrelated adult volunteer donor, a haploidentical transplantation donor or a cord blood unit. High-risk patients are frequently ASCTs are increasingly performed offered an ASCT because due to the improved availability the likelihood of a cure with of alternative donors and chemotherapy alone is very refinement of indications low. Currently an ASCT is an according to the NHS England established treatment for high- Clinical Commissioning Policy risk acute leukaemia. for Haematopoietic Stem Cell Patients who have a bone Transplantation. In addition, the marrow relapse following advent of the haploidentical stem initial chemotherapy treatment cell transplantation (HID-SCT), may benefit from a stem cell where the donor matches exactly transplant (SCT); however, this half of the HLA, offers another is not uniformly recommended. option for patients, although General procedure for ASCT in this option only accounts for ALL patients involves total body approximately 10% of ASCTs in the irradiation, because outcomes are UK. improved in patients who undergo Adults with Philadelphia transplant after achieving a low chromosome-negative ALL in MRD status. their first complete remission

Helpline freephone 08088 010 444 17 How is relapsed ALL treated? (cont.)

will benefit from an HLA-matched Adults with ALL who relapse have donor ASCT or a HID-SCT. a poor prognosis. Young adults Moreover, children with T-cell ALL less than 30 years old with a first benefit from ASCTs, including complete remission of two years HID-SCT. or more may have the chance of long-term survival; however, older Philadelphia chromosome- patients (>30 years) who relapse positive ALL patients who early do not have realistic survival have received a HLA-matched options with current therapies. donor ASCT compared to those who had a HID-SCT showed Despite the great improvements similar results in studies with in the treatment of ALL in children, children and adults. In a study with a five-year overall survival of of 82 Philadelphia chromosome- approximately 90%, the prognosis positive ALL Chinese patients, is still much lower for children HID-SCT was associated with a who have relapsed, compared meaningful lower relapse rate with newly diagnosed ALL. compared with HLA-matched donor ASCT (44.8 vs. 19.1%, If you would like some respectively), although overall survival times were the same. support or advice about your relapse, If an HLA-identical sibling donor you can speak to the is not available, the probability of finding a fully matched unrelated Patient Advocacy donor should be estimated to help team by calling inform the decision on whether 08088 010 444 or to search for an unrelated donor emailing support@ or find an alternative source leukaemiacare.org.uk of haematopoietic stem cells (haploidentical donor or cord blood unit). Prognosis

18 www.leukaemiacare.org.uk Helpline freephone 08088 010 444 19 Glossary

Allogeneic Stem Cell Transplant to stop the growth of cancer cells, either by killing the cells or by Transplant of stem cells from a stopping them from dividing. matching donor. Chromosomes Antibody Thread-like structures include Blood protein produced by the an individual’s genes, and are B-cell lymphocytes in response located in the nuclei of every to, and counteracting, a specific cell in the body. There are 46 antigen such as a bacteria, virus, chromosomes (23 pairs) in or foreign substance. humans. Autologous Stem Cell CNS3 status Transplant CNS3 status occurs when the Transplant of stem cells derived cerebrospinal fluid sample from part of the same individual. contains equal to or greater Blasts than 5 white blood cells/µL with identifiable blasts, or there is the These white blood cells are not presence of a cerebral (brain) fully developed and are called mass or cranial palsy. blasts or leukaemia cells. Complete Remission Bone Marrow Relapse Complete remission occurs when Bone marrow relapse is defined the following conditions have as the presence of 25% of been met: lymphoblasts or more in a bone marrow aspirate following the ••Blood cell counts returned to first complete remission. normal Central Nervous System (CNS) ••Less than 5% of blasts Part of the nervous system which (abnormal, immature, early includes the brain and spinal lymphocytes) are still present in cord. the bone marrow Chemotherapy ••There is no leukaemia present elsewhere in the body Drugs that work in different ways

20 www.leukaemiacare.org.uk Cranial Nerve Palsy Hypodiploidy Weakness and impaired function Hypodiploidy is having less (palsy) of one or more of the than the normal number of 46 twelve cranial nerves caused by chromosomes. tumours, trauma, impaired blood flow, and infections. The condition Lymph nodes may also be congenital. Components of the lymphatic system (part of the body’s DNA (deoxyribonucleic acid) immune system) that contain Thread-like chain of amino acids lymphocytes which produce found in the nucleus of each cell antibodies and macrophages to in the body which carries genetic digest dead cells. Lymph nodes instructions used in the growth, are swollen with cell fragments development and functioning of if infection or cancer occurs. the individual. Lymph nodes are located mainly in the spleen, but also in the neck, Genes armpit and groin. Genes are made up of DNA which stores the genetic information Minimal Residual Disease required to make human proteins. (MRD) Measure of the presence of Haploidentical Stem Cell leukaemia at a molecular level Transplantation (HID-SCT) rather than at a cell level. It Type of allogeneic transplant is measured using molecular of stem cells where the donor techniques such as flow matches exactly half of the cytometry and polymerase chain human leukocyte antigens. reaction analysis. Leukaemia Petechiae A group of cancers that usually Red or purple, flat, pinhead spots begin in the bone marrow under the skin. and result in high numbers of abnormal white blood cells known Philadelphia chromosome as blasts. (BCR-ABL1) BCR-ABL1 is a cancer gene formed

Helpline freephone 08088 010 444 21 Glossary (cont.)

by the fusion of chromosomes 9 Relapse and 22 [t(9;22) (q34;q11)]. BCR- A relapse is when a patient ABL1 is found in all patients with initially responds to therapy chronic myeloid leukaemia and but, after six months or more, some patients with ALL. response stops. This is also Platelets sometimes called a recurrence. Platelets are one of the types of Thymus Gland blood cells which help to stop Main organ of the lymphatic bleeding. system, located behind the Precursor Cell sternum and between the lungs, where the T-cell lymphocytes Precursor cells are a type of develop and mature. partially differentiated stem cell which has the capacity to Tyrosine Kinase Receptors differentiate into only one cell Receptors present in the type (B-cell or T-cell). membranes of all of the body’s Refractory (leukaemia) cells which contain the enzyme tyrosine kinase that carries Refractory leukaemia is a information to and from complex leukaemia that does not result cell networks. It functions as an in a remission or that gets ‘on’ or ‘off’ switch in many cellular worse within six months of the functions. last treatment. However, the leukaemia may be stable.

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

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