Purpose of study:
(Non-Down Syndrome: HR-ALL or VHR-ALL)
In the initial stage of treatment for ALL, called Induction, we try to remove all visible signs of leukemia and allow normal blood cells to be restored. This is called remission. The cancer fighting medicine (chemotherapy) given during Induction on this study is one of the current standard Induction treatments for HR-ALL (High Risk B-precursor Acute Lymphoblastic Leukemia). Five chemotherapy drugs are used during this part of treatment.
The purpose of this part of the study is to collect information about your leukemia that will be used to guide further therapy and to understand effects of Induction therapy on you. Information gathered on the AALL08B1 will be used to help further define your risk group and guide further therapy. (AALL08B1 is a biology study, required prior to the theraputic study AALL1131). Your doctor will know your final risk group by the end of Induction. You will be offered the chance to continue treatment on other parts of this study once your final ALL risk group is known.
The overall goal of this study is to collect information about your leukemia and about the effects of the first phase of treatment, called Induction.
Even though treatment success rates are very good for people with HR-ALL, some patients still have relapse of their leukemia. Therapy on this study attempts to decrease the number of people who relapse in the central nervous system. This is called CNS relapse.
The CNS is made up of the brain and spinal cord and the fluid that surrounds them. One of the ways doctors try to prevent CNS relapse is by giving some of the chemotherapy into the fluid surrounding the spine. Medicines given into the spinal fluid are given intrathecally or IT. This study looks at how well CNS relapse can be prevented in children with HR-ALL by comparing the use of 3 drugs (methotrexate, hydrocortisone, and cytosine arabinoside) given intrathecally. This is called triple intrathecal therapy or ITT. We will compare ITT to the standard use of 1 drug (methotrexate) given intrathecally (IT MTX). The use of ITT is experimental on this study. However, ITT has been given to many people will ALL and has been well tolerated. We do not know which approach is better. That is why we are doing this study.
This study also includes studies that aim to better understand the things that contribute to side effects of cancer treatment, and how to prevent them or reduce them as much as possible.
The overall goals of this study are to:
Other goals of this study are:
To better understand the effects of cancer treatment in people with HR-ALL.
(Down Syndrome: DS-ALL or DS HR-ALL)
In a recently completed COG study, several patients with DS HR-ALL died from infections during treatment, mainly during Induction and Maintenance. Infections and death are known possible complications of treatment, but more of these complications occurred in patients with Down syndrome.
On this study, Induction and Maintenance therapy (described below) have been changed from the usual treatments in an effort to decrease toxicity. We do not know if these changes will decrease toxicity. Therefore, we also will closely monitor patients, with the aim of reducing the number of unintended and unwanted results of treatment (serious side effects) and deaths among children and adolescents with DS HR-ALL.
Methotrexate is a cancer-fighting drug that is very important in the treatment of leukemia. During the Interim Maintenance phase of treatment methotrexate is usually given as High dose methotrexate. In “high dose” methotrexate therapy, the same dose of methotrexate is given a total of 4 times (every 2 weeks over a 9-week period). However, because subjects with DS are particularly sensitive to drugs like methotrexate, the High dose methotrexate on this study will be modified to a somewhat lower dose called Intermediate dose methotrexate. We do not know if intermediate dose methotrexate given during Interim Maintenance will be helpful for DS HR-ALL, and it may increase the side effects of treatment.
This study also aims to understand the biology of DS HR-ALL better, by testing blood or bone marrow for changes in certain genes. Genes are materials that determine the makeup of the body. We would to learn more about these abnormal changes in genes in patients with DS HR-ALL (called high risk genetic lesions). We would also like to look at levels of white blood cells in the blood (called absolute lymphocyte count) at the end of Induction therapy. This would help us learn more about DS HR-ALL, and may help us to guide therapy for patients in the future.
The overall goals of this study are to:
ther goals of this study are:
Who can participate:
Patients must have newly diagnosed B-precursor ALL. Patients with Down syndrome are also eligible.
Patients must not have received any prior cytotoxic chemotherapy for the current diagnosis of ALL or any cancer diagnosed previously, with the exception of steroids and intrathecal cytarabine for the current diagnosis of ALL. Patients cannot have secondary ALL that developed after treatment of a prior malignancy with cytotoxic chemotherapy.
Patients receiving prior steroid therapy may be eligible for AALL1131
Additional screening for eligibility will be required.
What will happen during the study:
(Non-Down Syndrome: HR-ALL or VHR-ALL)
People taking part on this study (subjects) will receive 1 of 2 different treatment plans (also called ‘arms’). The treatment plan that you receive is decided by a process called randomization. Randomization means that the treatment is assigned based on chance. It is a lot like flipping a coin, except that it is done by computer. The randomization process will occur after Induction therapy (at the time when your risk status is determined to be HR-ALL) but prior to the start of Consolidation therapy.
If you agree to this randomization, you will have an equal chance of being assigned to 1 of the 2 different arms. Some subjects will be randomized to receive treatment on Arm A; others will be randomized to receive treatment on Arm B for all phases of post-Induction therapy. The 2 treatment arms in this study are the same standard or regular therapy for people with HR-ALL except for differences in the type of intrathecal therapy subjects receive.
Arm A: Patients receive therapy that is standard including age adjusted intrathecal methotrexate.
This is the standard arm.
Arm B: Patients receive therapy that is standard with triple intrathecal therapy (methotrexate, hydrocortisone and cytosine arabinoside) instead of intrathecal methotrexate. This is the experimental arm.
People taking part on this study (subjects) will receive a standard treatment plan during Induction. Induction therapy will be given over 4 weeks.
A number of factors were used to identify you as having HR-ALL. These factors included the results of research tests (FISH, MRD and hypodiploidy) done on leukemia cells before the start of, and during Induction therapy, as well as your age and the presence or absence of leukemia cells in your spinal fluid or brain.
The treatment involves cancer fighting medicine called chemotherapy and radiation therapy for patients with testicular disease. Post-Induction treatment on this study is divided into 4 stages: Consolidation, Interim Maintenance, Delayed Intensification and Maintenance.
Female patients are expected to receive treatment on this study for about 2¼ years. Because males receive longer Maintenance therapy, males are expected to receive treatment on this study for about 3¼ years.
(Down Syndrom: DS-ALL or DS HR-ALL)
The treatment plan involves cancer fighting medicine called chemotherapy as well as radiation therapy for people taking part in this study (subjects) with leukemia cells in the testes. Treatment on this study will be given in the following phases: Induction, Consolidation, Interim Maintenance, delayed Intensification and Maintenance. Subjects are people who agree to participate in this study.
Studies have shown that subjects who have Down syndrome are more likely to suffer serious side effects from treatment with chemotherapy than subjects without Down syndrome. Subjects with Down syndrome are particularly sensitive to certain chemotherapy medications, such as methotrexate. To help lessen the side effects of methotrexate, you will be given a vitamin called leucovorin, every time you are given methotrexate into your spinal fluid except during Maintenance therapy. You will also be closely monitored throughout your treatment for various side effects. Additionally, you will be receiving treatment during Induction and post-Induction with the following modifications:
During Induction, subjects will receive modified therapy that is less intense than normal. Therapy will be given in such a way that subjects that do not need an additional drug, daunorubicin, will not have to be exposed to the side effects that this drug may have. This will be determined by a bone marrow test that will be done halfway into Induction therapy.
All subjects get the same treatment in the first half of Induction, except for the type of steroid used; which will depend on your age.
If you are less than 10 years old, the steroid dexamethasone will be used
If you are equal to or above 10 years old, prednisone will be used.
After all patients have received Induction treatment for 14 days, a bone marrow test will be done to assess your response to the treatment so far (called early response status). The remaining therapy you get for Induction will depend on your early response status, described below:
Rapid Early Responders (RER) these subjects respond quickly to treatment. The results of bone marrow tests show signs that the leukemia has been removed and these patients reach remission very soon after the start of treatment. Rapid early responders will therefore continue with Induction therapy as before, for the remainder of Induction therapy.
Slow Early Responders (SER) these subjects respond to treatment more slowly and take longer to reach remission. Also, once they reach remission, more therapy is needed to maintain that remission. Since SERs are at greater risk of the leukemia coming back, for the remainder of Induction therapy, they will continue with treatment as before, plus they will receive an additional drug called daunorubicin. The dose of daunorubicin that is given on this study is lower than that used on previous studies.
Because chemotherapy can make your blood counts low causing serious side effects like infections and bleeding, you will also get a drug called a myeloid growth factor (example filgrastim) that will help your counts to recover.
During Interim Maintenance, subjects with Down syndrome will be given intermediate dose methotrexate instead of high dose methotrexate because it is known that children with Down syndrome are more sensitive to this drug.
During Maintenance, all subjects will receive the drugs vincristine and prednisone. These drugs are known to have short and long term side effects. Long term side effects are harmful effects seen months or years after you have finished your treatment, and children with Down syndrome have had more serious side effects during Maintenance than other children. Therefore in this study, vincristine and prednisone will be given at regular 12 week intervals (called pulses) for children with Down syndrome, instead of 4 week intervals as will be given to other children on the study, in order to try and reduce these bad effects. In most COG ALL studies, boys are treated for about a year (12 months) longer than girls. In this study, boys will be treated for the same length of time as girls to reduce the risk of serious side effects during Maintenance treatment.
People in this clinical trial are expected to receive treatment on this study for about 2 ½ years. After treatment, you will have follow-up examinations and medical tests.
Who to contact:
PI: Mark Ranalli, MD