ALLTogether1 (ALL)

One of the medications a child with ALL will receive is PEGasparaginase. PEGasparaginase can cause a hypersensitivity reaction, causing the drug to disappear quickly from the blood. As a result, it will not work as well. During treatment, a standard blood sample is taken from time to time to measure how much PEGasparaginase is in the blood. If the amount of PEGasparaginase is very low, your child will be given a different type of asparaginase.

In this substudy, we want to see if there is a connection between the amount of the drug PEGasparaginase in the blood, its effect and any side effects the child may experience. For this we use the asparaginase levels that are standardly taken, but we also want to investigate whether the level immediately after the asparaginase injection (top level) influences the effect and side effects.

As part of treatment for ALL, children receive chemotherapy to prevent leukemia from returning to the brain. We call this therapy targeting the central nervous system (CNS). This consists of drugs that are administered with an epidural. We know that CNS targeted therapy is essential to cure leukemia in most children. What we do not know is exactly how much treatment is needed for each individual child. We would like to know:

• whether some children can be cured with less CNS-targeted therapy and

• whether, conversely, other children need more CNS-focused therapy to prevent the disease from returning to the CNS.

To do this, we need to develop better tests to detect leukemia in the CNS and to measure how quickly it responds to treatment. Currently, we look for leukemia cells in the spinal fluid with a microscope, but this is not accurate enough. In the CSF-FLOW study, we want to see if we can better measure CNS leukemia with other laboratory tests.

Because the child may experience side effects from treatment, we think it is important to know how a child feels during and after treatment, both physically and mentally. Therefore, we want to assess the quality of life during and after treatment. We do this by means of questionnaires in children as young as 4 years old.

Children treated according to the Standard Risk group can participate in the substudy Randomization 1 (R1). This substudy investigates whether in the Delayed Intensification treatment phase the drug doxorubicin can be safely omitted from treatment, and whether this reduces side effects.

The Delayed Intensification phase lasts seven weeks. During the first half of this phase, the child receives vincristine through the port-a-cath and dexamethasone through the tube or mouth. Also, chemotherapy is given via an epidural. Normally during this treatment phase, the drug doxorubicin is also given three times through the port-a-cath. We try to omit doxorubicin from this phase because it can cause serious side effects, such as infections.

In the second half of this treatment phase, the child is given two drugs: cytarabine and 6-mercaptopurine. This part of the treatment phase does not change.

Children treated according to the IR-low group can participate in the substudy Randomization 2 (R2). This substudy will investigate whether in the treatment phases Delayed Intensification and Maintenance certain medications can be safely omitted from treatment, and whether this reduces side effects.

The drugs in question are:

• doxorubicin, which is given in the Delayed Intensification phase

• vincristine in combination with dexamethasone, which is given in the Maintenance Treatment

The Delayed Intensification phase lasts seven weeks. During the first half of this phase, the child is given vincristine through the port-a-cath and dexamethasone by mouth or tube. Also, chemotherapy is given via an epidural. Normally during this treatment phase, the drug doxorubicin is also given three times through the port-a-cath at the same times as vincristine. We try to omit doxorubicin from this phase because it can cause side effects, such as serious infections.

The final phase of treatment is the Maintenance Treatment. This phase lasts the longest (about 1.5 years), but contains the least intensive drugs. These are two types of chemotherapy, methotrexate and 6-mercaptopurine, administered by mouth or tube. In addition, patients receive vincristine once a month (through the port-a-cath) and, for 5 days, dexamethasone (by mouth/tube).

In treatments given in other countries, it no longer seems necessary to add dexamethasone and vincristine to the Maintenance Treatment. These drugs increase the risk of mood swings and can cause side effects in the bones and nerves. We want to investigate whether we can safely omit vincristine and dexamethasone from treatment and whether this reduces the side effects of treatment.

Doxorubicin and vincristine/dexamethasone will not both be omitted as this would "double" the reduction of the intensity of treatment.

Children classified in the IR-high group can participate in this substudy. The purpose of this substudy is to see whether the addition of the drugs inotuzumab ozogamicin (InO) or 6-thioguanine (6TG) to standard Maintenance Treatment can reduce the risk of disease recurrence.

In this substudy, two new treatment options are being investigated in the Maintenance Phase:
   A) Adding the drug inotuzumab ozogamicin (InO) to standard Maintenance Treatment;
   B) Adding 6-thioguanine (6TG) to standard Maintenance Treatment (TEAM = Thiopurine Enhanced ALL Maintenance).

A) InO is a drug that binds to a substance on the surface of the leukemia cell (called CD22), and then releases a chemotherapy agent (calicheamicin) into the leukemia cell. CD22 is found only on leukemia cells and on some mature blood cells.

The drug InO is not yet approved in Europe for the treatment of ALL in children. It has been approved for the treatment of adults with ALL after the disease has recurred or if the disease has not responded well to initial treatment. There are ongoing studies on treatment with this drug in children in whom ALL has recurred, or in whom the disease has not responded well to initial treatment. In these, good results are seen and InO is well tolerated.

B) The drug 6-mercaptopurine - part of the standard Maintenance Treatment - is converted in the body to other substances, which are built into the DNA of the leukemia cell (=DNA-TG). A high concentration of DNA-TG is associated with a lower risk of disease recurrence. The concentration of DNA-TG can be increased by adding the drug 6TG to Maintenance Treatment. 6TG is approved for the treatment of children with ALL.

The purpose of this substudy is to see if treatment of children with Down Syndrome and ALL with the drug blinatumomab (Blina) causes fewer side effects and is more effective than standard chemotherapy.

Blina is not chemotherapy but immunotherapy. It is an antibody. Antibodies help the body's white blood cells defend against bacteria and viruses. Antibodies can also help in the defense against cancer cells. Blina acts as a connector, allowing the healthy immune cell to bind to the cancer cell. In doing so, it helps the healthy immune cell to clear away the cancer cell.

In studies done so far with Blina, it has been seen to be more effective than standard chemotherapy in the treatment of adults with relapsed (returned) ALL. In children and teenagers with relapsed ALL treated with Blina, also fewer side effects are seen than with treatment with standard chemotherapy. Therefore, we want to investigate whether this is also a better medicine for children with Down Syndrome and ALL.

Patients with certain genetic abnormalities - so-called ABL-class fusion genes - respond less well to standard chemotherapy and have a higher risk of disease recurrence compared with other ALL patients. The leukemia cells of these patients are genetically very similar to those of patients with another type of ALL, which we call Philadelphia chromosome-positive ALL.

Treatment with certain drugs (Tyrosine Kinase Inhibitors; TKIs) gives very good results when given right at the diagnosis of Philadelphia chromosome-positive ALL. Therefore, we also want to include such a TKI (in this case, imatinib) in the treatment of patients in whom an ABL-class fusion gene has been found, to reduce the risk of disease recurrence.

The goal of this substudy is to improve the treatment of ALL patients with an ABL-class fusion gene by adding imatinib (a TKI) to ALLtogether1 treatment. We will investigate whether more patients are cured and fewer patients get the disease back. We also want to do some additional laboratory tests to study how this drug works.

After the initial treatment phase of ALLTogether1 (Induction), the bone marrow is examined to determine how well the treatment is working. In the process, sensitive tests sometimes find residual leukemia cells; this is called minimal residual disease or MRD. In most children, these residual leukemia cells are gone by the end of the next phase of treatment (Consolidation). But in a small proportion of children, MRD remains present; we call this MRD-positive. These children could benefit from additional treatment options, including CAR T-cell therapy. This is immunotherapy with "Chimeric Antigen Receptor T cells."

CAR T-cell therapy is not part of the treatment under the ALLTogether1 protocol, but may be offered in other trials. In order to determine as soon as possible which children are eligible for CAR T-cell therapy, we want to expand the MRD analysis that is done by default in the ALLTogether1 protocol at the end of the Consolidation Phase. One additional MRD assessment (CAR T pre-screening) will then be done and evaluated in a central laboratory. This will also avoid the need for an additional bone marrow puncture at a later time for this CAR T pre-screening.

The results of the MRD analysis give the treating physician the information needed to decide whether CAR T-cell therapy is recommended. If so, the doctor will explain in detail how CAR T-cell therapy works and what the next steps are.

After the intensive treatment phases of ALLTogether1 (Induction, Consolidation, Intensification) comes the Maintenance Treatment. The purpose of this phase is to reduce the risk of the leukemia recurring after treatment ends. During the Maintenance Treatment, children receive 6-mercaptopurine (6MP), methotrexate (MTX), and chemotherapy through an epidural. This substudy associated with the Maintenance Treatment focuses on the medications 6MP and MTX.

The absorption of 6MP and MTX in the gut varies widely among people. Also, major differences exist in the processing of these drugs in the blood after they are absorbed from the gut. These differences in the absorption and processing of 6MP and MTX in the blood can affect the likelihood of the disease returning. Therefore, the child's treating physician will adjust the dose of 6MP and MTX during treatment, for example, when neutrophils (a certain type of white blood cells) in the blood become too low or when serious side effects occur. The aim of this substudy is to investigate whether the concentrations of 6MP and MTX in the blood can be used to improve the Maintenance Treatment.