Delayed Intensification Blog | Your Blog Won’T Get Traffic Unless You Do This 상위 27개 답변

당신은 주제를 찾고 있습니까 “delayed intensification blog – Your Blog Won’t Get Traffic Unless You do This“? 다음 카테고리의 웹사이트 Chewathai27.com/you 에서 귀하의 모든 질문에 답변해 드립니다: Chewathai27.com/you/blog. 바로 아래에서 답을 찾을 수 있습니다. 작성자 Neil Patel 이(가) 작성한 기사에는 조회수 10,158회 및 좋아요 446개 개의 좋아요가 있습니다.

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여기에서 이 주제에 대한 비디오를 시청하십시오. 주의 깊게 살펴보고 읽고 있는 내용에 대한 피드백을 제공하세요!

d여기에서 Your Blog Won’t Get Traffic Unless You do This – delayed intensification blog 주제에 대한 세부정보를 참조하세요

Your blog won’t get traffic unless you do this. Did you know there are over 1 billion blogs? Just for a moment, think about that. It means that there’s roughly one blog for every 7.5 people. Do we really need more content? At the. Do we really need more blogs? No, not really. And no matter what’re blogging about these days, it’s super competitive. Just think of it this way, there are over 1.2 billion results for the term auto insurance, just in the United States.
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Now, if you had to guess how many people do you think are searching for the term auto insurance within the United States each month? It’s 165,000 people a month. To put that in perspective, there are roughly 7,272 times more results than searches. And that’s just like every other topic on the web. It’s been beaten to death and no one cares for another auto insurance blog post.
So how do you get traffic to your blog when most things have already been written on? Because let’s face it, no one wants to read the same old stuff over and over again. You have to be fresh and no, I’m not saying that you have to create content that no one has ever written on before. Instead, I’m saying that you have to present the same old information in a new way.
For example, everyone already knows how fast a cheetah can run, so there’s nothing new there. But have you seen that information presented like this? Just look at that beautiful, animated graphic. Have you ever seen data presented like that?
Now, granted, if you can create content that’s new, it hasn’t been written on before and you think people will crave it, by all means, do that. And you should focus on that. But for a large chunk of your content, realistically, it’ll be on topics that people are already familiar with and have been written on before and what you’ll need to do is present that in a new way like that cheetah infographic or in any other format that people haven’t seen before. If you do that, you’ll get more back links, you’ll get the social shares, you’ll get more traffic.
Another blog that’s a great example of this is the Oatmeal. Years and years ago they started doing interactive infographics, quizzes, like how would you survive against a T-Rex when you’re chained to a bunk bed? It’s kind of crazy. No one really would be in that realistic scenario cuz T Rexes don’t exist anymore, but nonetheless, that’s fresh content.
Again, it doesn’t have to be new, it just has to be presented in a new way. and if you do that, you’ll get the back links, you’ll get the social shares, you’ll get tones of viral traffic cause everyone will be talking about it and you’ll start noticing that your blog will become more popular . And when you can, of course, write on new stuff that no one has ever heard or seen before.

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delayed intensification blog 주제에 대한 자세한 내용은 여기를 참조하세요.

Category: Delayed Intensification

Delayed Intensification is 56 days long and it is the fourth phase of frontline treatment. Frontline is the initial portion of the 3.5 year …

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Source: www.journeyofaleukemiawarrior.com

Date Published: 8/29/2021

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Consolidation, delayed intensification and high risk block …

Consolation, delayed intensification and high risk block treatment for childhood acute lymphoblastic leukaemia (ALL).

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Source: www.cancerresearchuk.org

Date Published: 4/26/2021

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Day 180: First Couple of Days of Delayed Intensification

Elliott went four weeks with no chemo, the longest since his original diagnosis. In that time he built up enough strength to start walking, his …

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Source: www.elliottblog.com

Date Published: 7/26/2021

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What is delayed intensification? Explained by FAQ Blog

Expert Answers: Delayed intensification, is a repeat of the first two months of induction and consolation in high-risk and very-high-risk ALL protocols …

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Source: faq-blog.com

Date Published: 10/29/2022

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Delayed Intensification Part 1 DONE! – Michele1218

A life blog featuring my favorite beauty and fashion trends, hauls, reviews, outfit of the days, healthy eating, recipes, mommy and baby …

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Source: michele1218.blogspot.com

Date Published: 1/19/2022

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Reduced-Intensity Delayed Intensification in Standard-Risk …

Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with …

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Source: ascopubs.org

Date Published: 7/22/2022

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Second half of Delayed… – Team L&B. Twins Battling Cancer

Second half of Delayed Intensification Bailey: Delayed Intensification Phase – Day 32 (of 56) Lily: 8+ weeks off treatment Bailey was able to resume…

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Source: www.facebook.com

Date Published: 7/19/2022

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Delayed Intensification – The Heavy Wait

There are a million and one different ways to help support your child’s body while experiencing Leukemia. Ranging from fleeing to Mexico and finding a …

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Source: theheavywait.com

Date Published: 1/5/2022

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1219 Days of Beating Cancer – UF Health

By late Monday afternoon, we were at Shands.” … Consolation, interim maintenance and delayed intensification lasted 10-11 months and …

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Source: ufhealth.org

Date Published: 5/21/2022

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Good News: Teen Enjoys Remission, Relationships at Golisano

And doctors have changed his chemotherapy treatment from a delayed intensification cycle to a maintenance cycle. Chemo will finally end for Lee on Sept.

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Source: www.leehealth.org

Date Published: 11/11/2021

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주제와 관련된 더 많은 사진을 참조하십시오 Your Blog Won’t Get Traffic Unless You do This. 댓글에서 더 많은 관련 이미지를 보거나 필요한 경우 더 많은 관련 기사를 볼 수 있습니다.

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주제에 대한 기사 평가 delayed intensification blog

• Author: Neil Patel
• Views: 조회수 10,158회
• Likes: 좋아요 446개
• Date Published: 2022. 6. 30.
• Video Url link: https://www.youtube.com/watch?v=fSOFzxu5m4M

What can I expect from delayed intensification?

Delayed intensification is similar to another induction and consolidation phase and lasts for 8 weeks. This phase is important because it can improve a child’s event-free survival, which is the period after treatment in which a patient does not experience cancer symptoms or recurrence.

What is intensification chemotherapy?

The second phase of chemotherapy is called “consolidation” therapy or “intensification” therapy. During this phase, the chemotherapy drugs are given in higher doses than those given during the induction phase.

Can leukemia come back after 15 years?

Patients who achieve a complete remission to initial treatment and then experience a cancer recurrence are said to have relapsed leukemia. Relapse of leukemia may occur several months to years after the initial remission; however the majority of relapses occur within two years of initial treatment.

What is Capizzi style methotrexate?

Introduction The Capizzi-style methotrexate (MTX) is an integral part of acute. lymphoblastic leukemia (ALL) treatment.

How long is delayed intensification?

Delayed intensification phase takes 6, 7 or 12 weeks depending on which risk group your child is in. The high risk blocks take about 3 weeks each. Your child may have between 3 to 6 blocks. Taking about 10 to 20 weeks in total.

Does hair grow back during maintenance?

Hair regrowth usually starts one to three months after maintenance starts or intensive chemotherapy ends. The color and texture may be different from the original hair. Straight hair may regrow curly; blond hair may grow back brown. Sometimes during maintenance, some children’s hair begins to thin or fall out again.

How many rounds of chemo is normal?

During a course of treatment, you usually have around 4 to 8 cycles of treatment. A cycle is the time between one round of treatment until the start of the next. After each round of treatment you have a break, to allow your body to recover.

What happens if induction chemo doesn’t work?

If AML doesn’t go away completely with induction treatment, sometimes a second, similar course of chemotherapy (chemo), often called reinduction, can be tried. If this isn’t helpful, treatment with other chemo drugs or more intensive doses of chemo may be tried, if the person can tolerate them.

What are the three phases of chemotherapy?

Can you live a long life with leukemia?

Chronic lymphocytic leukemia (CLL) can rarely be cured. Still, most people live with the disease for many years. Some people with CLL can live for years without treatment, but over time, most will need to be treated.

Can you be fully cured of leukemia?

As with other types of cancer, there’s currently no cure for leukemia. People with leukemia sometimes experience remission, a state after diagnosis and treatment in which the cancer is no longer detected in the body. However, the cancer may recur due to cells that remain in your body.

What were your first signs of leukemia?

What is Capizzi regimen?

Escalating intravenous methotrexate followed by a second chemotherapy drug called asparaginase (together known as the Capizzi regimen) has been an effective standard treatment for ALL for approximately two decades.

What does Capizzi mean in Italian?

The surname Capizzi is a name for person who was the chief of the head from the Italian personal name Capo.

What is the most intense chemo?

Doxorubicin (Adriamycin) is one of the most powerful chemotherapy drugs ever invented. It can kill cancer cells at every point in their life cycle, and it’s used to treat a wide variety of cancers. Unfortunately, the drug can also damage heart cells, so a patient can’t take it indefinitely.

How many chemo treatments needed for AML?

You’ll usually be given a combination of 2 or more chemotherapy drugs. Most people have 2 rounds of induction chemotherapy. The treatment will be carried out in hospital or in a specialist centre, as you’ll need very close medical and nursing supervision.

What are the most common side effects of chemotherapy?

Can chemo cure lymphoma?

Non-Hodgkin lymphoma is usually treated with chemotherapy or radiotherapy, although some people may not need treatment straight away. In a few cases, if the initial cancer is very small and can be removed during a biopsy, no further treatment may be needed.

Day 180: First Couple of Days of Delayed Intensification — Elliott Fights Leukemia

This past Monday Elliott’s cell counts were high enough for him to start delayed intensification. It is bittersweet. We are excited that to move forward with this next phase of treatment, and getting closer to the end, but it is also distressing to see just how quickly the side effects of the medication have manifested.

Elliott went four weeks with no chemo, the longest since his original diagnosis. In that time he built up enough strength to start walking, his appetite returned, he gained 2.5 pounds, and his hair began to grow back. In less than 24 hours we have already seen his energy level plummet. He also seems to have lost his appetite, but that may have more to do with the horrible taste of the medications, and less to do with their effects on the body. On a positive note, Elliott has already shown us that this phase of chemo is not going to keep him down. He found the energy to color with Laurel, which resembles a contact sport when she is involved.

AboutKidsHealth

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Acute lymphoblastic leukemia: chemotherapy phases

Acute Lymphoblastic Leukemia: Chemotherapy Phases

A

English

Oncology

Child (0-12 years);Teen (13-18 years)

Body

Skeletal system

Drug treatment

Adult (19+)

NA

2018-03-06T05:00:00Z

10.0000000000000

52.8000000000000

1312.00000000000

Flat Content

Health A-Z

Learn what happens during each of the five phases of chemotherapy for acute lymphoblastic leukemia (ALL).

The goal of treatment is to completely destroy leukemic cells and stop the bone marrow from producing any more cancerous cells.

To treat ALL, your child’s chemotherapy is divided into five different phases.

Key points

• Chemotherapy for children with acute lymphoblastic leukemia (ALL) is divided into induction, consolidation, interim maintenance, delayed intensification, and maintenance phases.
• There is a high likelihood that leukemia will return if maintenance phase is not completed.

Each phase differs in length and the type of medicines that are used. Some of the drugs listed for each treatment phase may differ slightly from your child’s protocol.

1. Induction phase

The aim of induction therapy is to destroy leukemic cells and get your child into morphologic remission. This means that less than 5% of your child’s bone marrow cells are leukemic and a normal amount of white blood cells, red blood cells, and platelets are being produced.

How is your child’s progress monitored during induction?

Your child’s doctor will perform a bone marrow test on the 29th day of your child’s treatment. This test is called a minimal residue disease (MRD) test. It looks at how well the treatment is destroying the leukemia cells by measuring the number of leukemia cells left inside your child’s bone marrow. This information will help the oncologist decide on your child’s ALL risk category and subsequent treatment plan.

It is important to note that the MRD test can only measure detectable leukemia cells. We know that even if the MRD test is negative, there are still undetectable leukemia cells after completing induction chemotherapy. This is why more phases of treatment are required.

What do the MRD values mean?

• If your child is MRD positive, they still have detectable leukemia cells inside their bone marrow.
• A negative MRD value (less than 0.01%) means that your child may still have leukemic cells left in their bone marrow, but we cannot detect these leukemic cells by current methods.

Depending on the MRD value, your doctor might change the treatment plan to make sure your child receives the most effective course of treatment. Children with positive MRD are categorized as high-risk or very high-risk ALL. They may undergo more intense chemotherapy or may be recommended to have a bone marrow transplant (BMT).

How long does induction last?

Induction therapy usually lasts for 29 days followed by a 1-week rest from chemotherapy.

During induction, drugs will be given intravenously (IV) or through an intrathecal (IT) or orally (by mouth):

• If a drug is given intravenously, an IV is used to deliver medicine directly into your child’s vein. To set up an IV, a nurse will place a hollow needle into a vein in your child’s hand or arm. Once they have found they vein, they remove the needle and insert the IV. The IV is a hollow tube that is placed in the vein and attaches to a longer tube, which connects to the IV pump and delivers medicine into your child’s vein.
• Intrathecal (IT) is an injection into the spinal fluid around your child’s spinal cord by a nurse or a doctor. It is given as a single injection or by using a catheter and a pump.

Medicines used during induction

Usually, all of the following drugs are given during induction:

• cytarabine (ARA-C), intrathecal (IT)
• methotrexate (MTX), IT
• dexamethasone (DEX) or prednisone (PRED), by mouth
• vincristine (VCR), intravenous (IV)
• asparaginase (ASP) or PEG-asparaginase (PEG-ASP), intravenous (IV)
• daunorubicin (DAUN), IV; this medicine is only used for children with high-risk ALL

2. Consolidation phase

After completing induction therapy, your child starts the consolidation phase. Although there may not be detectable leukemia cells in your child’s blood or bone marrow at the end of induction, there still might be some leukemia cells that doctors cannot detect. This is why the treatment continues.

The consolidation phase lasts for 4 to 8 weeks, depending on the ALL risk type and protocol.

Your child may take the following medicines:

• methotrexate (MTX), IT
• mercaptopurine (6-MP), by mouth
• vincristine (VCR), IV
• cyclophosphamide, IV
• cytarabine (ARA-C), IV
• PEG-asparaginase, IV

3. Interim maintenance phase

After consolidation, the next phase is interim maintenance. This phase aims to destroy any leukemic cells left in your child’s marrow or blood. This phase lasts about 8 weeks.

Your child may take the following medicines:

• methotrexate (MTX), IV and IT
• mercaptopurine (6-MP), by mouth
• vincristine (VCR), IV

4. Delayed intensification phase

Delayed intensification is similar to another induction and consolidation phase and lasts for 8 weeks. This phase is important because it can improve a child’s event-free survival, which is the period after treatment in which a patient does not experience cancer symptoms or recurrence.

During delayed intensification phase, your child may take the following medicines:

• methotrexate (MTX), IT
• dexamethasone (DEX), by mouth
• thioguanine (6-TG), by mouth
• vincristine (VCR), IV
• doxorubicin (DOXO), IV
• PEG-asparaginase (PEG-ASP), IV
• cyclophosphamide (CPM), IV
• cytarabine (ARA-C), IV

5. Maintenance phase

In maintenance phase, there are still no detectable leukemic cells in your child’s marrow or blood. However, this phase must be completed because cancerous cells may still be present, even if we cannot see them. Maintenance occurs for all leukemia patients after completing the previous phases, unless doctors suspect your child has relapsed.

Each cycle of maintenance lasts for 84 days. Cycles are repeated until the duration of therapy from the start of interim maintenance is 2 years for girls and 3 years for boys.

As with all phases following induction therapy, the goal of maintenance is to consolidate and maintain remission. There is a high likelihood that the leukemia will return if this phase is not completed. For this reason, it is very important that your child takes all medicines as instructed.

During maintenance, your child takes all of the following medicines:

• methotrexate (MTX), IT
• dexamethasone (DEX) or prednisone (PRED), by mouth
• 6-mercaptopurine (6-MP), by mouth
• methotrexate (MTX), by mouth
• vincristine (VCR), IV

What is maintenance like?

Your child receives intravenous chemotherapy on a schedule determined by your child’s protocol. They take chemotherapy medicines by mouth every night at home, and come into the hospital to:

• receive blood-work to check complete blood counts (CBC) every 2 to 4 weeks
• take vincristine intravenously every 4 weeks
• start a course of steroids (dexamethasone or prednisone) every 4 weeks
• receive a lumbar puncture so that doctors can give your child intrathecal chemotherapy, once every 3 months

Blood work is important because doctors need to make sure that the amount of your child’s white blood cells (neutrophils) are not too high or too low. If they are too low, then the chemotherapy is killing too many marrow cells, making your child neutropenic and at risk for developing an infection. If the amount of neutrophils is too high, then the therapy is not killing enough hidden leukemia cells. For this reason, making sure your child takes 6-mercaptopurine orally every day and methotrexate orally every week, without missing doses, is essential to ensure your child stays in remission and reduce the risk of relapse.

How can you help your child keep a healthy lifestyle during maintenance?

During maintenance, your child needs to maintain a healthy lifestyle. Encourage your child to eat nutritious food and to participate in daily exercise. Physical activity is very important to minimize your child’s risk of becoming overweight or obese, which can be a long-term side-effect of the treatment. In addition, exercise can also prevent muscle wasting (decrease in muscle mass) and help maintain bone health during treatment phases when steroids need to be used. Typically, there are no restrictions on physical activity during maintenance chemotherapy, even though the central line is still in place. Talk to your child’s treatment team to discuss your child’s physical activity options.

For more information, please visit Good nutrition during leukemia treatment.

Acute lymphoblastic leukemia: chemotherapy phases

False

Leukemia and Lymphoma Society

Because of acute lymphoblastic leukemia’s (ALL’s) rapid growth, most patients need to start chemotherapy soon after diagnosis.

Chemotherapy drugs kill fast-growing cells throughout the body including cancer cells and normal, healthy cells. The damage to normal, healthy cells can cause side effects. Yet, not everyone experiences side effects the same way.

ALL treatment consists of:

Induction Therapy

The first phase of treatment is induction therapy. The goal of induction therapy is to destroy as many cancer cells as possible in order to achieve (induce) a remission. Typically, initial therapy requires a hospital stay of 4 to 6 weeks.

Induction regimens for ALL generally use a combination of drugs that include

Vincristine (Oncovin®)

Anthracyclines (daunorubicin [Cerubidine®], doxorubicin [Adriamycin®])

Corticosteroids (prednisone, dexamethasone)

With or without pegaspargase (PEG-L asparaginase, Oncaspar®) and/or cyclophosphamide (Cytoxan®)

At the end of induction therapy, doctors will check to see whether the patient has achieved a complete remission. A complete remission is achieved when

No more than 5 percent of cells in the bone marrow are blast cells

No blasts are found in the blood

Blood cell counts are back to normal

All signs and symptoms of ALL are gone.

To see a list of standard drugs and drugs under clinical study to treat ALL, order or download The Leukemia & Lymphoma Society’s free booklet Acute Lymphoblastic Leukemia (ALL) in Adults

For information about the drugs listed on this page, visit Drug Listings.

Minimal Residual Disease (MRD)

Even when a complete remission is achieved, some leukemia cells that cannot be seen with a microscope may still remain in the body. The presence of these cells is referred to as “minimal residual disease (MRD).” Patients who have achieved remission after initial treatment for this type of ALL, but have MRD are at increased risk of disease relapse.

It is important to get tested for MRD after achieving remission. The tests used most often to detect MRD are flow cytometry, polymerase chain reaction (PCR), and next-generation sequencing. These three tests typically use samples of bone marrow cells, but in some cases blood samples can be used. The tests are much more sensitive than standard tests that examine cell samples with a microscope. It is often recommended that MRD testing be done after the completion of induction therapy. Recommendations for additional MRD testing depend on the treatment regimen used.

For patients in remission but who test positive for MRD, blinatumomab (Blincyto®) may be prescribed.

Postremission Therapy

“Postremission therapy” refers to ALL treatments given to patients after their disease is in a complete remission. Residual leukemia cells remain after remission, so the optimal treatment for ALL patients requires additional intensive postremission therapy. Individual factors that may influence the treatment approach include:

Age

Ability to tolerate intensive treatment,

Cytogenetic findings

Availability of a stem cell donor.

Post-remission therapy consists of two phases:

Consolidation therapy (given in cycles over 4 to 6 months)

Maintenance therapy (given for about 2 years for adults and 2-3 years for children).

Consolidation Therapy. The second phase of chemotherapy is called “consolidation” therapy or “intensification” therapy. During this phase, the chemotherapy drugs are given in higher doses than those given during the induction phase. The combination of drugs and the duration of therapy for consolidation regimens vary but can consist of combinations of drugs similar to those drugs used during the induction phase. Generally, several chemotherapy drugs are combined to help prevent the leukemia cells from developing drug resistance.

Some of the drugs used in the consolidation treatment phase include

High-dose methotrexate

Cytarabine

Vincristine

6-mercaptopurine (6-MP)

Cyclophosphamide

Pegaspargase

Corticosteroids (prednisone, dexamethasone)

Maintenance Therapy. The third phase of ALL treatment is called “maintenance.” The goal of maintenance therapy is to prevent disease relapse after induction and consolidation therapy. Most maintenance drugs are given orally and, typically, patients are treated in an outpatient setting. They receive lower doses of chemotherapy drugs and, as a result, tend to have less severe side effects. In some cases, postremission chemotherapy also includes drugs that were not used during induction treatment.

Most maintenance regimens include

6-mercaptopurine (administered daily)

Methotrexate (administered weekly)

Periodic doses of vincristine and corticosteroids

Central Nervous System Prophylaxis

Although the presence of leukemia cells in the cerebrospinal fluid at diagnosis is not common (found in only 3 to 7 percent of cases), a large percentage of patients (50 percent or more) eventually develop CNS leukemia without the routine administration of CNS-targeted therapy, also called “central nervous system prophylaxis.” CNS prophylaxis is administered to prevent leukemia cells from spreading to the area around the brain and the spinal cord and is typically given to all patients throughout the entire course of ALL treatment—during the induction phase, the consolidation phase and the maintenance phase.

Central nervous system-directed therapy may include

Intrathecal chemotherapy. In this treatment, anticancer drugs are injected into the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord. These drugs may include methotrexate, cytarabine and corticosteroids (prednisone, dexamethasone).

Systemic chemotherapy. In this treatment, anticancer drugs travel through the blood to cells all over the body. These drugs may include high-dose methotrexate, intermediate-/high-dose cytarabine and pegaspargase.

Cranial irradiation. Radiation therapy to the brain.

Related Links

Relapsed or Refractory Adult ALL

Relapsed or Refractory Adult ALL

Overview

Patients with progressive or relapsed adult ALL remain curable despite failing initial treatment. Patients failing treatment can be divided into two broad categories. Patients who fail to achieve an initial complete disappearance or remission of their cancer following a complete course of remission induction chemotherapy treatment are referred to as “induction failures”. Patients who achieve a complete remission to initial treatment and then experience a cancer recurrence are said to have relapsed leukemia. Relapse of leukemia may occur several months to years after the initial remission; however the majority of relapses occur within two years of initial treatment. Refractory is a term that implies that patients have failed at least one treatment regimen after a relapse.

A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the treatment of relapsed or refractory adult ALL. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

Patients who fail induction treatment or relapse have essentially two choices of therapy. Additional treatment with chemotherapy is rarely curative and some patients will choose a palliative approach where drugs are administered in non-toxic doses to keep the disease under control for as long as possible. In this situation, the emphasis is on the quality of life and supportive care measures.

The alternative approach is to receive more intensive treatment or participate in clinical studies in an attempt to produce a complete remission. For some patients, an allogeneic stem cell transplant offers a possibility for control or cure of adult ALL. Other patients may choose to participate in clinical trials evaluating new treatments.

An allogeneic stem cell transplant is a procedure that is performed to repair the damage caused by high-dose chemotherapy. High-dose chemotherapy (HDC) kills more cancer cells than lower-dose conventional chemotherapy. Unfortunately, HDC also kills more normal cells, especially the blood-producing stem cells in the bone marrow. Stem cells are immature cells produced in the bone marrow that eventually develop into red blood cells, which provide oxygen to tissues; white blood cells, which fight infection; or platelets, which aid in blood clotting. The treatment strategy utilizing stem cell transplant is an attempt to restore the blood-producing stem cells after HDC has reduced them to dangerously low levels. When stem cells reach critically low levels from HDC, complications such as anemia, infection and bleeding can occur. Thus, it is imperative to restore stem cell levels as quickly as possible. An allogeneic stem cell transplant utilizes stem cells collected from a related or unrelated donor or from umbilical cord blood. For more information go to Allogeneic Stem Cell Transplant.

Patients with relapsed ALL who choose to have more aggressive therapy should be treated on protocols which are evaluating novel therapies as the current treatments for this phase of ALL do not result in high long-term survival rates. Protocols sponsored by the National Cancer Institute are carried out by cooperative groups in the US. These groups have protocols for all phases of treatment of ALL and include:

Cancer and Leukemia Group B (CALGB): http://www.calgb.org/

Eastern Cooperative Oncology Group (ECOG): http://www.ecog.org/

Southwest Oncology Group (SWOG): http://www.swog.org/

Information about National Cancer Institute sponsored protocols for ALL can be obtained at cancer.gov.

The information provided here describes some of the commonly used strategies and some of the investigative studies being carried out to improve treatment of patients with ALL who fail conventional therapies.

Treatment of Patients Failing Induction

Patients who are unable to achieve a complete remission with initial standard chemotherapy are rarely curable with additional standard chemotherapy treatments. In addition, high-dose chemotherapy and autologous stem cell transplant is rarely a treatment option because the bone marrow contains many leukemia cells. Since the current complete remission rate is over 90% in adults with ALL, few patients will fall into this category. Currently, the best treatment for patients failing induction treatment is an allogeneic stem cell transplant. A transplant can be performed in first relapse or after an attempt to produce a remission with a chemotherapy regimen different than that used for induction. Patients with adult ALL who receive a related or unrelated donor stem cell transplant in other than first complete remission have a long-term disease-free survival of 27%.1 The best survivals are seen in those patients who achieve a remission with reinduction chemotherapy and the worst survivals are in those who were refractory to attempts to produce a remission.

Reinduction chemotherapy with standard chemotherapy drugs has been effective in producing complete remissions in some patients, but there are no cures without an allogeneic stem cell transplant.

Treatment of Patients Relapsing after an Initial Remission

Patients with adult ALL that relapses after an initial complete remission can be cured with standard chemotherapy, autologous stem cell transplant, or allogeneic stem cell transplant.

The timing of relapse in relation to initial diagnosis and treatment is important. Patients who relapse while receiving, or shortly after receiving, chemotherapy are unlikely to be cured with further chemotherapy. However, if the relapse occurs many months or years after discontinuing maintenance chemotherapy, many can achieve a second remission with re-institution of chemotherapy similar to that used in initial treatment. However, few of these patients are cured without a stem cell transplant.

Standard-dose chemotherapy can induce a complete remission in 10%-30% of adults, but few patients are cured. The average duration of survival is 5-6 months and less than 5% of adult patients survive 5 years after relapse.

Regimens Used for Reinduction Treatment

A number of regimens have been evaluated for the treatment of patients with relapsed ALL. A few of the more common regimens will be listed below:

High-Dose Idamycin® (idarubicin) and Cytosar® (cytarabine):Various doses and schedules of Idamycin and Cytosar have been used to treat relapsed adult ALL over the past two decades. One of the more recent studies reported a complete remission rate of 44% with a median disease-free survival of 6 months.2

Cytosar, Amsidine® (amsacrine) and VePesid® (etoposide): Researchers from France have reported a complete remission rate of 40% with the combination of Cytosar, Amsidine and VePesid in patients with relapsed ALL, with a disease-free survival of 12% at three years.3 All long-term survivors had received an allogeneic stem cell transplant after remission induction.

Drugs Recently Approved by the US Food and Drug Administration

Two new drugs that are analogs of the commonly used chemotherapy drug 6-mercaptopurine have been approved by the FDA for treatment of refractory patients with ALL: Clolar® (clofarabine) and Arranon® (nelarabine, 506U78).4

Arranon: Arranon is a drug which has resulted in a 50% response rate in children with refractory T-cell ALL.5 This drug has now been incorporated into remission induction and consolidation therapy for children with T-cell ALL.6

Clolar: Clolar is a new drug that has been primarily evaluated in children with ALL who relapsed after primary therapy.7

Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation from a related or unrelated donor or by using umbilical cord blood offers the best chance of long-term disease-free survival in patients with relapsed ALL. A large study recently reported that patients with adult ALL who receive a related or unrelated donor stem cell transplant in other than first complete remission have a long-term disease-free survival of 27% (see reference 1).

Treatment of Philadelphia Chromosome-Positive ALL

Most current patients with ALL in relapse will have failed Gleevec® (imatinib). However, for patients not receiving up-front Gleevec this drug can be used in salvage regimens. Researchers from France have reported that high-dose Gleevec combined with vincristine and dexamethasone produced complete remissions in 90% of patients with Philadelphia chromosome-positive ALL in relapse.

Some patients with Philadelphia chromosome-positive ALL become refractory to Gleevec due to the development of mutated leukemic clones. However, there are now two drugs currently approved by the US Food and Drug Administration (FDA) for treating adult ALL patients that are refractory to Gleevec: Sprycel® (dasatinib) and Tasigna® (nilotinib). There are other tyrosine kinase inhibitors in the drug development pipeline that have not yet been approved by the FDA, including bosutinib (SK1606).

Sprycel® (dasatinib): Sprycel is a newly developed tyrosine kinase inhibitor that is more than 300 times more active than Gleevec for inhibition of Bcr-Abl (the abnormal protein produced by the Philadelphia chromosome). Sprycel can produce complete cytogenetic remissions in patients with ALL who are refractory to Gleevec.8,9 In addition, Sprycel is more effective than Gleevec for the treatment of Philadelphia chromosome-positive ALL that involves the central nervous system (CNS).10 This is because Gleevec does not get into the central nervous system while Sprycel does.

Tasigna® (nilotinib): Tasigna is another tyrosine kinase inhibitor which has more potency than Gleevec. Tasigna produces significant remissions in patients with adult ALL who are refractory to Gleevec.11, 12

Strategies to Improve Treatment of Relapsed or Refractory Adult ALL

The development of intensive multi-agent chemotherapy induction regimens, advances in stem cell transplantation, improvements in supportive care, and patient and physician participation in clinical studies have resulted in steady progress in the treatment of adult ALL. The following strategies are currently being evaluated alone or in combination for the purpose of further improving treatment.

Increased Dose Intensity: Because higher doses of chemotherapy kill more leukemia cells than lower doses, many doctors have advocated increasing the dose or dose intensity of chemotherapy drugs as a way to improve remission and cure rates of patients with ALL. Increasing the dose intensity can be accomplished by increasing the number of doses of drugs in remission induction therapy, increasing the dose intensity of post remission therapy, or by administering very high-dose chemotherapy supported with stem cell transplantation as part of the overall treatment strategy. Increasing dose intensity may improve treatment outcomes, but is also associated with increased side effects; patients should directly inquire about these side effects.

New Drug Development: All new drugs for the treatment of patients with ALL are tested first in patients with relapsed or refractory disease. When they are found to be effective, they are then evaluated in remission induction regimens.

New Tyrosine Kinase Inhibitors

Gleevec is a tyrosine kinase inhibitor that was designed specifically for the treatment of leukemia associated with the Philadelphia chromosome abnormality. This drug has revolutionized the treatment of Philadelphia chromosome-positive ALL. However, drug resistance occurs and patients with ALL can fail treatment. Therefore, there is considerable research into the development of new tyrosine kinase inhibitors that can overcome resistance to Gleevec. There are two drugs currently approved by the US Food and Drug Administration (FDA) for treating adult ALL patients that have failed Gleevec: Sprycel® (dasatinib) and Tasigna® (nilotinib). There are other tyrosine kinase inhibitors in the drug development pipeline that have not yet been approved by the FDA, including bosutinib (SK1606).

Bosutinib (SK1606): Bosutinib is a drug that is still in phase I-II testing but it is also more potent than Gleevec. Preliminary studies show that this agent has significant activity in adults with ALL who are refractory to Gleevec.13 Taken together it appears that there will be many new drugs for the treatment of Philadelphia chromosome-positive adult ALL, which may make allogeneic stem cell transplantation less of a necessity.

Monoclonal Antibody Therapy

Monoclonal antibodies directed at tumor antigens have made a major impact in the treatment of cancer over the past two decades. The major advantage of monoclonal antibody therapy is that the toxicities are not the same as for chemotherapy and when added to chemotherapy there is little increase in side effects. There has been little progress in the development of monoclonal antibodies useful for the treatment of adult ALL. However, this situation may be changing. Researchers from New York University have reported that epratuzumab, a humanized monoclonal antibody that targets CD22 antigen, is effective alone or in combination for the treatment of ALL.14 This study showed that epratuzumab could be safely added to chemotherapy with improved responses in patients with advanced ALL. The Children’s Oncology Group plans to add epratuzumab for induction in children with high-risk ALL.

There is emerging evidence that the widely used anti-CD20 antibody Rituxan® (rituximab) has activity in some patients with ALL. A recent study has suggested that CD20 is upregulated in many cases of ALL making this disease a target for Rituxan.15 There are already reports of children with ALL responding to single-agent Rituxan or Rituxan in combination with chemotherapy.16 A study from MD Anderson Cancer Center has reported that the addition of Rituxan to intensive chemotherapy improved the outcomes of adult patients with ALL who were CD20-positive.17 This is expected to be an area of intense research in the near future.

Monoclonal Antibody Conjugated with Toxins

Mylotarg® (gemtuzumab ozogamicin) is an antibody to CD33 that is conjugated (joined) with a cytotoxic (cell-killing) antitumor antibiotic. This antibody conjugate is approved by the US FDA for the treatment of patients with acute myeloid leukemia (AML) who have failed other therapies. A small fraction of patients with ALL also have leukemia cells that are CD33 positive and Mylotarg has been effective in treating children with CD33 positive ALL.18 Experience with treating adult patients with CD33 positive ALL is limited.

Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal delivery of therapy at its planned dose and schedule. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects resulting from cancer and its treatment are appropriately managed. For more information, go to Managing Side Effects.

Strategies to improve treatment of patients who fail remission induction are also discussed in the section on Allogeneic Stem Cell Transplant.

References

1 Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared to unrelated transplant in first complete remission. Journal of Clinical Oncology 2004;22:2816-2825. 2 Tedeschi A, Montillo M, Strocchi E. High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: A pharmacokinetic and clinical study. Cancer Chemotherapy Therapeutics Pharmacology 2007;59:771-779. 3 Reman O, Buzyn A, Lheritier V, et al. Rescue therapy combining intermediate-dose cytarabine with amsacrine and etoposide in relapsed adult lymphoblastic leukemia. Hematology Journal 2004;5:123-129. 4 Larson RA. Three new drugs for acute lymphoblastic leukemia: nelarabine, clofarabine, and forodesine. Seminars in Oncology 2007;34:513-520. 5 Berg SL, Blaney SM, Devidas M, et al. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology Group. Journal of Clinical Oncology 2005;20:3376-3382. 6 Dunsmore K, Devidas M, Borowitz MJ, et al.: Nelarabine can be safely incorporated into an intensive, multiagent chemotherapy regimen for the treatment of T-cell acute lymphocytic leukemia (ALL) in children: a report of the Children’s Oncology Group (COG) AALL00P2 protocol for T-cell leukemia. Blood 2006;108 abstract 1864, 7 Kearns P, Michel G, Neiken B, et al. BIOV-111 a European phase II trial of clofarabine (Evoltra® in refractory and relapsed childhood acute lymphoblastic leukemia. Blood 2006;108: abstract number 1864. 8 Brave M, Goodman V, Kaminskas E, et al. Sprycel for chronic myeloid leukemia and Philadelphia chromosome positive acute lymphoblastic leukemia resistant or intolerant of imatinib mesylate. Clinical Cancer Research 2008;14:252-369. 9 Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. New England Journal of Medicine. 2006;354:2531-2541. 10 Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome positive leukemia. Blood 2008;112:1005-1012. 11 Kantarjian H, Giles F, Wunderle L, et al.Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.The New England Journal of Medicine. 2006;354:2542-2551. 12 Piccaluga PP, Paolini S, Marinelli G, et al. Tyrosine kinase inhibitors for Philadelphia chromosome positive adult acute lymphoblastic leukemia. Cancer 2007;110:1178-1186. 13 Gambacorti-Passerini C, Blummedorf T, Kantarjian H, et al. Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or AML who failed imatinib. Proceedings from the American Society of Clinical Oncology Conference. Chicago/IL. Abstract # 7006. 14 Raetz EA, Cairo MS, Borowitz MJ, et al. Chemoimmunotherapy reinduction with epratuzumab with acute lymphoblastic leukemia in marrow relapse: a Children’s Oncology Pilot Study. Journal of Clinical Oncology. 2008;26:3756-3762. 15 Dworzk MN, Schumich A, Printz D, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood 2008;Epub on September 9. 16 Gokbuget N and Hoelzer D, Treatment with monoclonal antibodies in acute lymphoblastic leukemia: current knowledge and future prospects. Annals of Hematology 2004;83:201-205. 17 Thomas DA, Faderl S, O, Brien et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 2006;106:1569-1580. 18 Chevallier P, Mahe B, Garand R, et al. Combination of chemotherpay and gemtuzumab ozogamicin in adult Philadelphia positive acute lymphoblastic leukemia patient harboring CD33 expression. International Journal of Hematology 2008:209-211.

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What is delayed intensification? Explained by FAQ Blog

What is delayed intensification?

Last Update: May 30, 2022

This is a question our experts keep getting from time to time. Now, we have got the complete detailed explanation and answer for everyone, who is interested!

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Delayed intensification, is a repeat of the first two months of induction and consolidation in high-risk and very-high-risk ALL protocols that includes some new agents (substituting dexamethasone for prednisone, doxorubicin for daunorubicin, and 6-thioguanine for 6-MP and repeating others).

How long is delayed intensification?

Delayed intensification lasts approximately eight weeks. Maintenance therapy is aimed at keeping your child in remission and destroying any leukemia cells that may remain in your child’s body.

What are the three phases of chemotherapy?

First phase — induction chemotherapy. Second phase — consolidation chemotherapy. Third phase — maintenance chemotherapy.

How long is maintenance for leukemia?

Maintenance occurs for all leukemia patients after completing the previous phases, unless doctors suspect your child has relapsed. Each cycle of maintenance lasts for 84 days. Cycles are repeated until the duration of therapy from the start of interim maintenance is 2 years for girls and 3 years for boys.

What is intensification therapy?

Intensification therapy is used to kill any cancer cells that may be left in the body. It may include radiation therapy, a stem cell transplant, or treatment with drugs that kill cancer cells. Also called consolidation therapy and postremission therapy.

Michele1218: Delayed Intensification Part 1 DONE!

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Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-

In the era of improved risk assignment, the question of the adequate chemotherapeutic intensity needed to ensure consistently low relapse rates was again addressed in a cooperative prospective trial jointly conducted by two large leukemia study groups—Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and Berlin-Frankfurt-Münster (BFM)—in AIEOP-BFM ALL 2000. The randomized trial compared standard delayed intensification (P-II) with a reduced-intensity regimen (P-III) in a cohort of standard-risk (SR) patients with favorable treatment response defined by PCR-MRD. Herein, we report the results of this trial.

In former trials, the ALL–Berlin-Frankfurt-Münster (BFM) study group demonstrated the importance of delayed intensification in the treatment of patients with low-risk ALL. The reintensification element protocol II (P-II) significantly improved the outcome of high-risk patients in ALL-BFM 76. 15 The reintensification element (protocol III [P-III]) also was implemented for low-risk patients in ALL-BFM 79. 16 , 17 ALL-BFM 83 focused again on reduction of treatment burden in low-risk patients by testing treatment with and without P-III, which yielded results in favor of reinduction (10-year probable event-free survival [pEFS] rate, 81 ± 5% v 56 ± 6%). 16 , 18

With increasing survival rates, therapy-related morbidity and mortality as well as long-term sequelae have increasingly moved into focus. 8 , 9 Especially for patient groups with the most favorable prognosis, several leukemia study groups have strived for a reduction of treatment burden without jeopardizing outcome. 10 – 14

Over the past decades, the prognosis for children and adolescents with acute lymphoblastic leukemia (ALL) has improved considerably. Advances were mainly accomplished through refinement of biologic characterization, risk group assignment, and risk-stratified treatment. 1 – 4 The assessment of minimal residual disease (MRD) has introduced unsurpassed precision in the differentiation between patients with a high risk of relapse and those with a low risk. 5 – 7 Prospectively developed in the 1990s, MRD measured by immunoglobulin/T-cell receptor gene rearrangement polymerase chain reaction (PCR-MRD) was implemented for risk stratification in the trial, Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients with Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000). 2 , 3 , 6

The objective of this randomized trial was to prove noninferiority of the reduced-intensity treatment compared with standard treatment. The main analysis was planned as a per-protocol evaluation of 4-year DFS. All randomly assigned patients were included in this analysis, but patients who switched trial arms were included in the treatment arm actually given. In addition, an intent-to-treat analysis was performed. The Kaplan-Meier method was used to estimate survival probabilities; differences between groups were compared by log-rank test. 23 Cumulative incidence functions for competing events were constructed by the method of Kalbfleisch and Prentice and were compared with Gray’s test. 24 , 25 The Cox proportional hazard regression model was used for univariable and multivariable analyses. 26 A sample size of 1,024 randomly assigned patients was considered appropriate to assess noninferiority (∆ < 4%) with 90% power under the assumption of a 96% 4-year DFS in the reference arm. Two interim analyses were planned 3 and 4 years after start of inclusion. For safety reasons, the interim analysis was a log-rank test of difference instead of the equivalence test planned for the final analysis. The primary outcome was disease-free survival (DFS) because all patients were in CR at random assignment. DFS was defined as the time from random assignment to the date of last follow-up or first event. Events were relapse, secondary neoplasm, or death from any cause. Secondary end points were overall survival (OS) defined as time to death from any cause, or last follow-up, and treatment-associated toxicities. P-III was shorter than P-II (duration, 28 v 49 days), and its cumulative drug doses were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide compared with P-II. An outline of the SR treatment of AIEOP-BFM ALL 2000 is shown in Figure 1 , with drug doses also listed in the Data Supplement. P-II and P-III are split into two parts. The first part lasts from day 1 to 29 in P-II and from day 1 to 14 in P-III, whereas the second part lasts from days 36 to 49 in P-II and from days 15 to 28 in P-III. Details on stratification, prognostic impact of MRD, and results of the random assignments during induction (dexamethasone 10 mg/m 2 /day v prednisone 60 mg/m 2 /day) have been published previously. 2 , 3 , 22 Criteria for cranial irradiation are listed in the Data Supplement. Only SR patients were eligible for random assignment. They were assigned to receive either the experimental, less-intensive P-III or the standard P-II as delayed intensification. Random assignment was performed centrally by each country’s data center in accordance with random permuted blocks. This randomization was stratified by allocation to a preceding random assignment (dexamethasone v prednisone) and treatment center. 22 Risk group assignment to the high-risk group in AIEOP-BFM ALL 2000 was based on genetic characterization of ALL (presence of BCR-ABL1 , KMT2A-AFF1 ) and slow cytologic and molecular response to treatment (prednisone poor response, no CR on day 33, or MRD ≥ 5 × 10 −4 on day 78). In the absence of the aforementioned high-risk criteria, patients were assigned to the SR group if MRD was negative on days 33 and 78 with at least two markers with a sensitivity of 1 × 10 −4 . The remainder of the patients without high-risk criteria was assigned to the medium-risk group. Good response or poor response to a 7-day prednisone prephase plus one intrathecal dose of methotrexate were defined as < 1.0 × 10 9 /L and ≥ 1.0 × 10 9 /L blasts in peripheral blood, respectively. Complete remission (CR) was defined as < 5% blasts in regenerating bone marrow at the end of induction treatment and the absence of extramedullary disease. Relapse was defined as either recurrence of ≥ 25% lymphoblasts in bone marrow or localized leukemic infiltrate at any site after having achieved CR. Patients 1 to 17 years of age with ALL in one of the participating centers in Italy, Germany, Austria, and Switzerland were registered in the AIEOP-BFM ALL 2000 trial after written informed consent from their guardians. Routine initial diagnostics were cytology, immunophenotyping, and molecular genetic screening for the presence of ETV6-RUNX1 , BCR-ABL1 , and KMT2A-AFF1 ( MLL-AF4 ) fusion transcripts. Response assessment was performed by early cytologic assessment as well as by PCR-MRD on the basis of immunoglobulin and T-cell receptor gene rearrangements.. The respective standard procedures have been published previously. 2 , 3 , 7 , 18 - 21 If analyzed separately for the first and the second phases of P-II and P-III, life-threatening adverse events were mostly observed in the first phase of P-II, whereas patients treated with P-III suffered from adverse events more frequently in the second phase of P-III. The median time needed until start of the second part of P-III or P-II was 15 days (n = 184 with data available) and 44 days (n = 173 with data available), respectively; 15 and 36 days were the expected time according to protocol, respectively. The incidence of death during remission was comparable, with 0.9 ± 0.4% (n = 5) and 0.7 ± 0.3% (n = 4) for P-III and P-II, respectively. The same applies for the number of adverse events, which was essentially the same in the two arms ( Table 2 ). Life-threatening events, however, were slightly more likely to happen with P-II (n = 10) than with P-III (n = 7). An interaction between the initial corticosteroid in induction and outcome after random assignment has not been observed ( Fig 4 ). Outcome by National Cancer Institute (NCI) criteria was an 8-year pDFS rate of 91.6 ± 1.4% versus 92.8 ± 1.3% ( P = .36), a CIR rate of 7.0 ± 1.3% versus 6.2 ± 1.2% ( P = .49), and an 8-year OS rate of 97.9 ± 0.7% versus 98.1 ± 0.7% ( P = .77) for NCI SR for P-III and P-II, respectively. For NCI high risk, the 8-year pDFS rate was 82.9 ± 3.1% versus 90.4 ± 2.7% ( P = .041); CIR rate, 13.0 ± 2.8% versus 7.5 ± 2.5% ( P = .07); and 8-year OS rate, 91.3 ± 2.3% versus 97.7 ± 1.3% ( P = .021) for P-III and P-II, respectively. Secondary malignancies occurred in seven patients who received P-III (myelodysplastic syndrome (n = 2); CNS tumor (n = 2); acute myeloid leukemia (n = 2); and non-Hodgkin lymphoma (n = 1) and in four patients who received P-II (myelodysplastic syndrome (n = 2); acute myeloid leukemia (n = 1); and solid tumor (n = 1). This finding corresponds to an 8-year cumulative incidence rate of secondary malignancy of 1.3 ± 0.5% and 0.6 ± 0.4% for patients given P-III and P-II, respectively ( P = .37; Table 1 ). The patterns of relapse with respect to time after diagnosis were different after P-III and P-II. The proportion of early relapses (ie, within 2.5 years after diagnosis) was higher in P-III than in P-II (P-III, 19 [38.0%] of 50 relapses; P-II, 10 [28.6%] of 35 relapses); the same occurred for late relapses (2.5 to < 5 years after diagnosis; P-III, 23 [46.0%] of 50 relapses; P-II, 10 [28.6%] of 35 relapses), but a significantly higher proportion for very-late relapse (≥ 5 years after diagnosis) was observed in patients treated with P-II (P-III, eight [16.0%] of 50 relapses; P-II, 15 [42.9%] of 35 relapses; P [χ 2 ] = .022). These differences of treatment outcome held for virtually all clinical and biologic subgroups, although in many subgroups the differences did not reach statistical significance ( Figs 4A to 4C ). ETV6-RUNX1 status and age at diagnosis represented the only exception. Eight-year pDFS rates of patients with ETV6-RUNX1 –negative ALL were 86.2 ± 1.9% versus 91.1 ± 1.6% ( P = .037) and for patients with ETV6-RUNX1 –positive ALL, 94.5 ± 1.7% versus 94.4 ± 1.8% ( P = .74) for P-III versus P-II, respectively ( Figs 5A and 5B ). Analogous results held for age at diagnosis. For patients 1 to 10 years of age, the 8-year pDFS rate was 90.7 ± 1.4% versus 92.4 ± 1.2% ( P = .26), and for patients age ≥ 10 years, 81.6 ± 4.0% versus 90.3 ± 4.1% ( P = .04) for P-III versus P-II, respectively ( Figs 5C and 5D ). After a median follow-up of 8.6 years, analysis per treatment given revealed a 4-year probability of DFS (pDFS ± SE) rate of 91.8 ± 1.1% in the reduced-intensity P-III arm (n = 584) and of 95.8 ± 0.8% in the P-II arm (n = 579; P = .04) on the basis of the occurrence of 62 versus 42 events, respectively ( Fig 3 ). The lower limit of the one-sided 95% CI for the pDFS rates was −6.4%, which is far below the noninferiority margin of −4%, ( P = .005 for difference of the 4-year pDFS estimates). The respective results at 8 years were 89.2 ± 1.3% and 92.3 ± 1.2% for pDFS ( P = .041) and 8.7 ± 1.2% and 6.4 ± 1.1% for cumulative incidence of relapse (CIR; P-III v P-II, P = .09; Fig 3 ). The 8-year OS rate was 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). The intent-to-treat analysis gave almost identical results (Data Supplement). From July 1, 2000, to June 30 (July 31 for AIEOP), 2006, 4,937 patients were enrolled in AIEOP-BFM ALL 2000, of whom 98 were not eligible for evaluation ( Fig 2 ). Among 1,346 SR patients eligible for random assignment, 182 were not assigned. The remaining 1,164 patients entered the randomized comparison; 581 children were allocated to the experimental arm P-III and 583 to the standard arm P-II. We observed no significant differences in initial patient characteristics among randomly assigned versus nonrandomly assigned patients as well as between the two arms analyzed by intention to treat or treatment given (Data Supplemental). DISCUSSION Section: Choose Top of page Abstract INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION << REFERENCES The attempt to reduce chemotherapy burden by choosing P-III as a lower-intensity delayed intensification in patients considered to be at low relapse risk did not succeed because outcome results were inferior to those obtained with the standard treatment. DFS data showed a significantly higher proportion of events in the experimental arm, especially for patients who were ETV6-RUNX1 negative or ≥ 10 years of age. In addition, the expected benefit of reduced-intensity treatment in terms of acute toxicity and rates of second malignancy could not be demonstrated. In fact, toxicity seems to be virtually the same in both treatment arms. A possible explanation for this observation is a less stringent handling of patients in P-III by the treating physicians, which is probably attributable to an underestimation of the impact of this treatment element. This hypothesis is supported by the significantly shorter treatment delay between both parts of the respective treatment phase (2 days in P-III v 14 days in P-II). Patients treated with P-III thus experienced a higher dose density than patients treated with P-II. Considering the higher number of relapses in patients treated with the less-intensive P-III, at least a subpopulation in the SR group was fairly undertreated with P-III. This refers particularly to the inferior outcome of patients ≥ 10 years of age and those with ETV6-RUNX1 negative precursor B-cell ALL, which suggests a greater effect in subsets with known unfavorable characteristics despite the very favorable early response depicted by highly sensitive PCR-MRD. In patients in the prognostically more favorable subgroups, such as those with ETV6-RUNX1–positive ALL and those 1 to 6 years of age at diagnosis, the hazard ratios for the incidence of relapse did not indicate an increase in the relapse rate, with the disadvantage of treatment reduction possibly being negligible (Fig 4B). The same can be seen in patients treated with dexamethasone during induction. The current randomization was designed on the basis of the results of the ALL-BFM 81 and ALL-BFM 83 trials, which were the first by our study group that introduced a reintensification regimen called protocol 3 in the SR groups. Furthermore, these two trials documented the distinct importance of delayed intensification for the prevention of relapse.1,18,27 Hence, in subsequent trials, reintensification became an integral element of ALL treatment by using the more intensive version of reintensification (P-II) from ALL-BFM 86.1,28 In the current trial (AIEOP-BFM ALL 2000), P-III was randomized against the latter to find an approximation toward a less-intensive, but still-effective treatment. Most recently, the Dutch Childhood Oncology Group (DCOG) reported the results of its study DCOG ALL10 with nonrandomized treatment reduction for SR patients during delayed intensification.11 The risk stratification criteria in this trial were similar to those in our trial. Treatment of SR patients was also comparable except for the reduced delayed intensification phase, which was considerably more reduced in intensity in that trial than in P-III. With reduced-intensity chemotherapy at a median follow-up of 80 months, 194 patients had a 5-year pEFS rate of 93.1 ± 1.9% and 5-year CIR rate of 6.4 ± 1.85%. The outcome results in this rather small cohort were interpreted as improvement compared with historical controls of the DCOG, and therapy reduction was declared as safe by study criteria. However, the pEFS was inferior, although not significant, to the results of the historical MRD-SR group as reported by the International BFM Study Group5 (5-year pEFS, 98%; SE, 2%; n = 55; P = .08). Of note, the rates of 5-year pEFS and 5-year CIR in the DCOG study were in between the respective results of P-III (5-year pDFS, 90.6 ± 1.2% [Δ = 2.5%]; 5-year CIR, 7.5 ± 1.1% [Δ = 1.1%]) and P-II (5-year pDFS, 94.9 ± 0.9% [Δ = 1.8%]; 5-year CIR, 4.1 ± 0.8% [Δ = −2.3%]) of the AIEOP-BFM ALL 2000 trial. This finding leaves open the question of whether the reduced intensity in the DCOG study is really noninferior to standard treatment with P-II. In the study Malaysia-Singapore ALL 2003 s, risk stratification was likewise based on PCR-MRD by basically using the same risk stratification criteria as in our and the DCOG ALL10 protocols. SR patients were treated with a nonrandomized reduced therapy on the backbone of the ALL-Intercontinental BFM 2002 protocol.13,29 The treatment included a three-drug induction without anthracyclines as well as a reduced reinduction roughly comparable to P-III as reported here. With a rather short median follow-up of 3.38 years, the SR group of 172 patients had a 6-year pEFS rate of 93.2 ± 4.1% and a 6-year OS rate of 95.4 ± 3.3%, which depicts major improvement with the reduced-intensity treatment approach compared with preceding results of this study group along with a lower incidence of fatal and/or life-threatening treatment-related events. With the lack of a randomized approach, however, these improvements hardly could be differentiated from general improvements in quality of treatment and supportive care. A randomized approach was chosen in the protocol of the British study group trial UKALL 2003, where 521 low-risk patients assessed by NCI criteria and PCR-MRD were randomly assigned to receive either one or two delayed intensification courses.12 With a median follow-up of 57 months, a difference in 5-year pEFS rate of 1.1% was reported (94.4% v 95.5%). The 95% CI of the difference was −5.6% to 2.5%. The authors concluded that the primary end point of the randomization (to rule out a 7% reduction in EFS) was achieved. With the noninferiority margin of 4% in the current trial, this would not be true. Defining a reasonable noninferiority margin is always a matter of debate. Another randomized treatment question about delayed intensification was asked by the US Children’s Oncology Group. Comparability with the aforementioned trials and our study, however, is even more limited because MRD was not used for risk stratification.10 The authors demonstrated that the addition of a second delayed intensification in the treatment schedule of NCI SR patients with rapid early cytologic marrow response did not offer an advantage in terms of 5-year pEFS and OS rate (90.9 ± 1.3% and 97.1 ± 0.8% v 90.5 ± 1.3% and 95.4 ± 3.8% for single and double delayed intensification, respectively). In summary, both of the latter-cited trials—UKALL 2003 and COG 1991—revealed the feasibility of treatment reduction in patients with the most favorable prognosis in a randomized approach. Discrepancies with the results presented here might be explained by a fairly different treatment approach. A higher treatment intensity in the reduced intensity arm with single delayed intensification, which is comparable with P-II in the current study, presumably is a critical threshold that has not been reached. Differences in the risk stratification approaches also hamper comparability with the current trial.11,13,28 As a future perspective, a constant refining of biologic subtypes and treatment response is warranted to ensure the best possible treatment stratification throughout study groups. Insertion of novel drugs in chemotherapeutic regimens and implementation of targeted therapies, such as leukemia-specific antibodies, hopefully will take their place in the treatment of SR leukemia and thus enable a reduction of conventional drugs. In particular, by sparing anthracyclines and alkylating agents, the reduction of acute and long-term toxicity could be achieved. However, as the results of the presented trial demonstrate, future development should be implemented carefully by means of randomized trials designed to recruit sufficiently large cohorts to enable detection of clinically relevant differences.

Delayed Intensification – The Heavy Wait

There are a million and one different ways to help support your child’s body while experiencing Leukemia. Ranging from fleeing to Mexico and finding a holistic cancer clinic to indulging on hospital cafeteria milkshakes at every appointment, the choices are vast. You can also spend hours, upon hours, (upon hours) reading the literature on the… Continue reading Integrative Choices Part 1: Food →

1,219 Days of Beating Cancer

Ann Collett used to dread 7:30 p.m.

At a time when many mothers across Gainesville were putting their young children to bed, Ann was preparing her son’s nightly chemo treatment.

William, an eighth-grader at Queen of Peace Catholic Academy, had been fighting acute lymphoblastic leukemia since he was just 10 years old. Forty months of treatment later, William officially beat pediatric cancer on Sept. 14.

In May of 2017, William was an “avid sports enthusiast,” playing basketball, running cross country and participating in track and field for his school. He was finishing fourth grade and was, by all accounts, a healthy kid.

“Everything just sort of came out of nowhere,” Ann recounts. “We went to our family pediatrician, Mary Grooms, M.D., FAAN, [Monday morning]. By late Monday afternoon, we were at Shands.”

William had been slowing down and getting headaches and bruises in recent weeks. The Colletts would come to find that these were signs associated with leukemia.

When William was diagnosed with acute lymphoblastic leukemia at UF Health Shands Children’s Hospital, Ann and husband Tom were shocked. Although they had known William was under the weather, cancer had been the last thing on their minds.

“He had been running a 5k just a couple of weeks before,” Ann said. “It was all kind of surprising.”

Ann and Tom are both active in the Gainesville community through various charities, such as Climb for Cancer and Stop Children’s Cancer. They had attended numerous local events supporting families battling pediatric cancer, with Tom even emceeing some of them as a Gator IMG Sports Network commentator.

Now, they were that family.

Following his diagnosis, William stayed at UF Health for almost two weeks. The first 30 days of his treatment — known as the “induction” phase — were focused on getting him into remission. With leukemia, remission can be achieved relatively quickly.

The next phases of William’s treatment focused on ridding the body of stray leukemia cells. Consolidation, interim maintenance and delayed intensification lasted 10-11 months and involved several hospitalizations.

While neutropenic fever is not uncommon with chemotherapy, every fever resulted in a trip to the UF Health Shands Pediatric E.R. for William. Because of his immunocompromised state, each fever was to be treated as if it were an infection.

Ann recalls that one of these fever-related E.R. trips turned into a 12-day hospital stay. For William, these stays were especially hard without his beloved Shih-Tzu-Yorkshire-terrier mix, Heartley. Upon returning home from his hospital trips, William would immediately find Heartley in his lap.

Being in one of the more intense phases of his treatment, William stayed out of school for most of his fifth-grade year, keeping up with classes and homework at home. This setback, however, did not stop William from maintaining his placement in advanced math classes.

“They would send his work home, teachers would record classes for him and offer one-on-one tutoring,” Ann said. “We would go to school so he could have lunch with his friends, or if there was a special event, we would go so he could participate.”

Around a year after his diagnosis, William entered the maintenance phase of his treatment, where he was able to “semi-resume” his life and return to school. By now, William was 11 and finishing elementary school.

For the next 28-29 months, William would receive monthly infusions, almost-monthly spinal taps and daily chemotherapy at home.

Ann recalls her son’s insistence that he resume playing on his school’s sports teams. One day, William was receiving a lumbar puncture, and a few days later he was running cross country, she said.

When COVID-19 hit the U.S. in March, the Colletts were already ahead of most Americans when it came to sanitizing protocols.

“COVID did not bring anything new into our world,” Ann said. “We’ve long been using antibacterial wipes and gel and just being very cautious about doors [and] being near people who are sick.”

In fact, 2020 has been “joyful” for the Collett family, despite its faults.

Sept. 14, 2020, had been marked on Ann’s calendar for years. This would be the day that William would be done with his treatments and officially be cancer-free. Not even a pandemic could tarnish this milestone for the Colletts.

When that day was only 100 days away, Ann said the reality of it finally began to sink in. When that day came, the Colletts could not control their excitement.

On Sept. 14, in the UF Health Children’s Healing Garden, Ann, Tom, William, sister Magen, William’s grandparents, family friends and William’s care team all gathered for a socially distanced bell-ringing ceremony. William Slayton, M.D., professor and chief of the division of pediatric hematology/oncology, gave a short speech and led songs and chants with his colleagues.

“It’s for the parents and for the child,” Slayton said of the ceremony. “The bell-ringing signifies the end of the treatment, but also the beginning of the rest of the person’s life.

Ann remembers how excited she was as she stood with her family in the garden, smiling and clapping for William and his care team. One of her friends commented after the event that Ann’s legs “would not stop going” and that it looked like she was going to jump for joy.

“The nurses on Unit 41 — most all of them were there when we started,” Ann said. “The PAs and ARNPs who are up in that department, they have just been amazing to work with.”

William’s team of pediatric hematology/oncology specialists included Slayton; John Fort, M.D., clinical associate professor; Stephanie Bryan, PA; Constance Stichweh, ARNP; and William Higgins, PA. This care team, plus Deborah Ringdahl, clinical case manager, made 40 months of treatment “as fun and as uplifting as possible,” according to Ann.

As William rang the bell signifying the end of his leukemia treatments, the garden erupted into cheers and applause. Ann, Tom, Magen and William embraced, holding each other tightly, before Slayton awarded William with a certificate, trophy and — to William’s delight — a brand new basketball.

“William faced his leukemia with a really great attitude,” Slayton said. “It never really seemed like the leukemia was holding him down.”

Slayton said he will remember William for the “really colorful and interesting” shoes and socks his patient would wear to appointments. “Swag” was a good word for it, Slayton remarked.

Following the ceremony, the Colletts were met at home with an elaborate drive-by parade. Cars were lined down the block, decorated with balloons and homemade signs, some shooting confetti out of their windows.

“More than one person said to me, ‘We needed this… not just for William, but in the midst of what we’re going through in 2020, we needed a celebration,’” Ann said.

William is building his immune system back up at home, the invisible burden of 7:30 p.m. chemo treatments now lifted. He is hoping to be back at school before March of 2021.

With most of the family at home now, the Colletts have been occupying their time with a furry new family member: 1-year-old mini goldendoodle Auggie.

Auggie entered the Colletts’ lives in early March, full of personality. He is now in training to be a therapy dog.

“We have felt that Heartley made such a difference in William and his treatment,” Ann said. “We didn’t have access to our dog when we would be getting treatment… Once we can return to visiting people in the hospital, Auggie and I will be ready to roll.”

Ann said that living through her son’s “life-changing” diagnosis forced her family to “sift and shift” their lives: Sift through tasks, hobbies and relationships that were unfulfilling or draining, and shift whatever was left and prioritize that.

William’s 40-month battle with leukemia reaffirmed what mattered most to the Colletts: family, friends and faith, Ann said. It also encouraged them to take things day by day.

“You cannot look at the end at the very beginning. You could know what the end will be, but for me to imagine what that was like — 1,219 days from diagnosis to ringing the bell — that’s too much for a person to comprehend,” Ann said. “Just know that you’ll get there and focus on today.”

Good News: Teen Enjoys Remission

“It’s cancer.”

It’s a line we all dread hearing about ourselves or a loved one – and it’s especially difficult to hear and understand when a child is involved.

Lee Sullivan, now 13, was diagnosed with cancer in April 2019. It hasn’t been an easy ride for Lee and his family, who have been working hard and battling every day against T-cell acute lymphoblastic leukemia.

He has encountered several complications since diagnosis—the most recent in August when a fungal infection made him septic.

He spent three weeks on life support in the ICU at Golisano Children’s Hospital of Southwest Florida, where he was forced to spend his 13th birthday.

The good news? Lee is currently in remission. And doctors have changed his chemotherapy treatment from a delayed intensification cycle to a maintenance cycle.

Chemo will finally end for Lee on Sept. 12, 2021.

More good news? Lee has become an inspiration to Golisano staff members, who now consider him family. And the feeling is mutual.

“I can never thank all the doctors, nurses, technicians, chaplains, pharmacists, social workers, child life, volunteers, and pet therapists enough for the delicate care they provided to my sweet Lee,” said Tanya Sullivan, Lee’s mother. “They always make sure I am involved in his care and make sure I feel heard, which was extremely important to me.”

Tanya Sullivan said the treatment experience has been a positive one from the moment they walked in the front door at Golisano.

“The environment plays a huge role in our treatment because my son never dreads going (to Golisano) but rather looks forward to seeing all the people who always bring a smile to his face,” Tanya Sullivan said.

Lee has since been able to go home and only comes back to Golisano for treatment and visits.

“I’m one forever grateful mother because of the care team at Golisano. Lee’s siblings and I get to have him with us now because the great care and measures they took to save his life,” Tanya Sullivan said.

Relationships, connections, family, and inspiration – sometimes it’s all about finding hope in the darkest of times.

“It’s not about how far you have to go – it’s about how far you have come!” Lee wrote in the Cohen Family Gardens at Golisano Children’s Hospital.

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