Childhood Leukaemia

Blood cancer is the main cancer that affects children stealing their smiles and future dreams. Leukaemia and lymphoma are two types of blood cancer that can affect children and are, alone, accountable for half of childhood cancer cases, as Leukaemia comes in the first place and lymphoma in the third place of the most common paediatric malignancies1. The main difference between lymphoma and leukaemia is that the former starts in the lymphocytes and the latter in blood cells precursors2

Leukaemia is classified into acute (fast growing) and chronic (slowly growing) leukaemia. Given that chronic Leukaemia is rare in children, it will not be addressed in this article. Acute leukaemia is divided into Acute Myeloid Leukaemia (AML) and Acute Lymphocytic Leukaemia (ALL) where the former starts in myeloid cells and the latter in lymphoid cells3 .

ALL is the most common leukaemia type in children and has two main subtypes: Tcell ALL and B-cell ALL, where B-cell ALL is responsible for roughly 85% of ALL cases in children1,3. The incidence of ALL is very high at the age between 2 and 3 years old, and studies showed that this malignancy starts in the uterus. Whereas AML, is less common and starts in myeloid cells (cells responsible for the formation of granulocytes, monocytes and macrophages, erythrocytes, and megakaryocytes)3 AML has a peak of incidence in the first two years that declines to nothing from 2 to 6 years old1

Some risk factors of leukaemia are1,3:

1. Genetic syndromes like Down Syndrome.

2. Inherited Immune system problems such as Shwachman-Diamond syndrome and ataxia-telangiectasia.

3. Having siblings with leukaemia

4. Lifestyle and environmental risks. Some studies found an association between drinking alcohol in pregnancy and leukaemia. Also, exposure to radiation and immune system suppression are important risk factors.

Childhood leukaemia is characterised by the following signs and symptoms: Leukaemia starts in bone marrow and after excessive proliferations, leukaemia cells leave the bone marrow to the circulation. Having that said, signs and symptoms can be related to the malfunction of any of the cellular blood components, and can be3:

1. Related to the lack of red blood cells

● Tiredness, weakness and feeling cold

● Dizziness

● Short breath and pale skin

2. Infections and fever are symptoms related to the shortage of functional white blood cells

3. Bruises and bleedings, for example nose and gum bleeding, are common symptoms resulting from platelets shortage.

4. Leukaemia cells accumulation in other parts of the body can lead to other symptoms specific to the accumulation site such as bones, joints, or abdomen leading to their swelling and appetite loss, respectively. Furthermore, this accumulation can lead to swollen lymph nodes and thymus, causing, therefore, breathing issues and cough.

Surprisingly, leukaemia can lead to enlarged face and arms due to thymus enlargement, which, in turn, presses on the superior vena cava congesting the blood in the veins and preventing it from returning to heart. All that can lead to consciousness problems, as well as headache and dizziness.

5. Leukaemia can develop further and cause chloroma or granulocytic sarcoma which are dark rashes that result from AML spread in the skin.

Leukaemia treatment

Selecting leukaemia treatment regimen depends on many factors such as leukaemia’s type, child age, and having genetic or chromosomal changes. Given that ALL is more common than AML in children, the following part will focus on ALL treatment that is composed of four main classes4:

1. Chemotherapy: can either be systemic or regional, where the former means a general exposure of the body to chemicals, meanwhile the latter means local exposure like injecting drugs directly in the abdomen, cerebrospinal fluid, or a specific organ.

2. Radiation therapy: counts on an external source of x-ray. It is mainly used to prepare the body for stem cell transplant but is also important when the ALL is spread in the body.

3. Stem cells transplant requires a donor who donates stem cells to the cancer patient (receiver) see be the match. The main goal is replacing the malignant cells with healthy cells. Transplant starts after the completion of radio and chemotherapy regimens.

Advanced therapies of ALL5

Despite the good survival rates achieved by chemotherapy, its adverse effects are still devastating, and targeted therapy is an urgent need. Immunotherapy is an essential part of targeted therapy. In 2014, blinatumomab, and in 2017 inotuzumab ozogamicin and tisagenlecleucel were approved by the FDA.

Blinatumomab is a bispecific antibody that increases the toxicity of T-cells in the combat against cancer. By being bispecific, it can bind to the T-cells from one side and to an excessively expressed protein on cancer cells from another, therefore, bringing them closer to each other and facilitating the cytotoxic properties of T-Cells. Despite this advancement, cancer cells developed mechanisms to tolerate Blinatumomab as they can stop the expression of its target.

Inotuzumab Ozogamicin is an antibody conjugated to calicheamicin. After it binds to the cancerous cells, it is internalised and the active substance is released in the acidic environment of the lysozyme. Calicheamicin, in turn, is a potent antibiotic that intercalates in the DNA leading to cell apoptosis.

Kymriah® (tisagenlecleucel)6

It was approved by the FDA and EMA for the treatment of refractory and relapsed cases of B-cell ALL in paediatric and adults younger than 25 years old. Tisagenlecleucel is a Chimeric Antigen Receptor, the T-cells of the patient are engineered with a transgene encoding the chimeric antigen of CD-19 (a protein excessively expressed on malignant B-cells and not on normal ones), so they selectively recognize cancer cells and destroy them

Philadelphia chromosome and leukaemia: Philadelphia chromosome (Ph) is the first chromosomal abnormality found in leukaemia. It is very common in CML as it reaches up to 95% of cases, but very rare in AML (1%). Regarding ALL, Ph is very rare as it is found in 3% of childhood cases but is common in adults ALL and its incidence augments with age. Ph+ in Acute leukaemia is an indication of a bad prognosis7

This chromosome (infographic 3) results from breaks in chromosomes 9 and 22, and then the two broken pieces exchange places giving rise to the abnormal chromosome 22. ABL gene (infographic), a proto-oncogene found on chromosome 9, fuses with the BCR gene on chromosome 22 giving rise to the BCR-ABL hybrid gene. Proteins coded by this hybrid gene have deregulated TK activity that leads to excessive proliferation of immune cell precursors7 .

Many therapies have been developed to target Leukaemia’s TK and are called Tyrosine Kinase Inhibitors (TKI). Imatinib was the first selective TKI to be developed, but due to cancer resistance, Imatinib loses its efficacy so fast. More generations of TKI were developed to overcome the tolerance to Imatinib such as nilotinib and dasatinib (2nd generation) and Bosutinib (3rd generation)8

Author: Rahaf Alsayyed, EPSA Science Coordinator 2022-2023

Be The Match is operated by the National Marrow Donor Program, which conducts research on blood cancer survival and helps cure those with leukaemia, lymphoma, and other life-threatening diseases by facilitating bone marrow or cord blood transplants. Be The Match is the hub of a global transplant network that connects 446 leading centres worldwide, including 163 transplant centres in the United States and 48 international transplant centres.

NCODA and Be The Match have been working in partnership for the past 5 years with the goal of fundraising for blood cancer research and increasing donor participation. Thus far, NCODA has raised over $45,000 and attracted over 500 new donors to the registry. The majority of the donor registries emanated from NCODA Professional Student Organization (PSO) chapters hosting student-led bone marrow registration drives. In the past three years, four students have been matched as a direct result of NCODA PSO donor drives. Two of these students have donated their bone marrow and saved the life of a patient in need. NCODA PSO will look to host over 30 bone marrow registration drives in 2023 as we look to amplify our efforts to match more donors with

If you are interested in getting involved with NCODA and Be The Match’s mission, please visit: ncoda.org/be-the-match/ or scan the QR code below.

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