Prognostic Factors and Survival Rates for Childhood Leukemia

Children ages 1 to 10 years with B-cell ALL tend to have better cure rates. Children younger than 1 year and children 10 years or older are considered to have high-risk ALL. The outlook in T-cell ALL is not affected much by age.

Children with ALL who have very high white blood cell counts (greater than 50,000 cells per cubic millimeter) when they are diagnosed are at higher risk and need more intensive treatment.

Whether a child has B-cell or T-cell leukemia does not affect the overall outlook much for children today. However, some forms of ALL need more intense treatment for the best prognosis. T-cell ALL and Burkitt leukemia (a mature B-cell leukemia) tend to need more intense treatment than other forms of ALL to achieve and maintain remission (when there are no cancer cells in the blood or bone marrow).

Girls with ALL may have a slightly higher chance of being cured than boys, but as treatments have improved in recent years, this difference has shrunk.

Normal human cells have 46 chromosomes. Children are more likely to be cured if their leukemia cells have more than 50 chromosomes (called hyperdiploidy), especially if there is an extra chromosome 4 or 10. Hyperdiploidy can also be expressed as a DNA index of more than 1.16. Children whose leukemia cells have fewer than 44 chromosomes (known as hypodiploidy) have a less favorable outlook.

Translocations occur when chromosomes swap some of their DNA. Children whose leukemia cells have a translocation between chromosomes 12 and 21 are more likely to be cured. Those with a translocation between chromosomes 9 and 22 (the Philadelphia chromosome) or 4 and 11 tend to have a less favorable outlook. Some of these “poor” prognostic factors have become less important in recent years as treatment has improved.

Children whose leukemia goes into remission (major reduction of cancer cells in the bone marrow) within 1 to 2 weeks of chemotherapy have a better outlook than those whose leukemia does not. Having minimal residual disease (MRD), which is a very small amount of leukemia cells still detectable by sensitive lab tests, can also affect outlook. Children whose cancer does not respond well may be given more intensive chemotherapy.

Children with low-risk ALL:

• Are between ages 1 and 10 years
• Have white blood cell counts of less than 50,000 when they are diagnosed
• Have favorable gene changes and responded well to treatment early after diagnosis (within the first 1 to 2 weeks).

Initial treatment is successful for children in the low-risk group more than 95% of the time. If leukemia recurs, there are other options to treat and hopefully still cure the leukemia.

Children with average-risk ALL:

• Are ages 1 to 10 years old
• Have white blood cell counts of less than 50,000 when they are diagnosed
• Either respond quickly to treatment, or have favorable gene changes and respond a little slower but have no cancer cells at the end of induction treatment

For those in the average-risk group, initial treatment is successful about 90% to 95% of the time. A recent study adding an immunotherapy drug, called blinatumomab, to chemotherapy showed even better outcomes for children with average-risk ALL. If leukemia recurs, there are other options to treat, and hopefully still cure, the leukemia.

The high-risk ALL group consists of children:

• Ages 10 years or older or with white blood cell counts over 50,000 when they are diagnosed and that responded well to treatment.
• Ages 1 to 10 years with white blood cell counts of less than 50,000 who responded slowly to treatment, but still have no cancer cells on standard tests at the end of induction treatment (the first 4 weeks of treatment)
• With leukemia in the cerebrospinal fluid (CSF) or testicles at diagnosis.

ALL can be classified as high risk (instead of very high risk) in these children even when there is still a very small amount of cancer cells in the body after induction found on special, more sensitive, testing called minimal residual disease (MRD).

For those in the high-risk group, initial treatment is successful in 88% to about 90% of cases. Blinatumomab is now being used in high risk ALL too, which may improve these outcomes. If leukemia recurs, there are other options to treat and hopefully still cure the leukemia.

Very high-risk ALL is ALL that does not respond well to treatment, meaning the cancer does not respond or go away during the first 4 weeks of treatment (induction), or has unfavorable gene changes (such as KMT2A).

Infants, or children less than 1 year old at the time of diagnosis are also harder to treat and in the very high-risk group. Blinatumomab is being added in newer trials to treat infants, with improved outcomes. There may be open clinical trials specifically for infants to test new treatments and strategies.

For those in the very high-risk group, the risk of cancer coming back is more common than in other risk groups. Initial treatments are still successful in many cases, but more intense treatments such as stem cell transplant (also known as a bone marrow transplant) may be needed.

Normal human cells have 46 chromosomes. Children are more likely to be cured if their leukemia cells have more than 50 chromosomes (called hyperdiploidy), especially if there is an extra chromosome 4 or 10. Hyperdiploidy can also be expressed as a DNA index of more than 1.16. Children whose leukemia cells have fewer than 44 chromosomes (known as hypodiploidy) have a less favorable outlook.

Infants and children newly diagnosed with AML tend to have a better outlook than adolescents and young adults. Adolescents and young adults, aged 15 to 39, may be more likely to relapse (have cancer return after treatment) and have more side effects from treatment.

Children with AML whose white blood cell count is less than 100,000 cells per cubic millimeter at diagnosis tend to do better than those with higher counts.

Some types of AML tend to have a better outlook than others. For example, acute promyelocytic leukemia tends to have a better outlook than most other types of AML.

Specific gene or chromosome changes are important prognostic factors in AML. Researchers agree on low-risk gene changes in AML. There is some debate about other gene changes and whether they are adverse/high-risk or neutral—not having a major impact on outlook and treatment.

Favorable or low-risk gene changes in AML include:

• Translocations, or swapping of genes, between chromosome 8 and 21 [also noted as t(8;21), or RUNX1-RUNX1T1]
• An inversion in chromosome 16
• CEBPA gene changes
• NPM1 gene changes without FLT3-ITD

Some of the more commonly acknowledged adverse or high-risk gene changes in AML include:

• Missing a copy of chromosome 5 or 7, called monosomy 5 or monosomy 7
• Translocation of a specific part of chromosome 11, that involves a gene called KMT2A, with chromosome 4, 6 or 10
• FLT3-ITD gene changes [also noted as t(6;9)(p23;q34)]
• An inversion in chromosome 3

Children with Down syndrome who develop AML tend to have a good outlook if the child is 4 years old or younger at the time of diagnosis.

Children who first have a myelodysplastic syndrome or whose leukemia is the result of treatment for another cancer tend to have a less favorable outlook.

Children whose AML responds quickly to treatment (only one chemotherapy cycle needed to achieve remission) are more likely to be cured than those whose leukemia takes longer to respond or does not respond at all.

Children with AML that have favorable or low risk gene changes have a better outlook than those with other types of AML.

70-80% of these children will be cured with chemotherapy alone. If cancer recurs, there are other options to treat it such as stem cell transplant (also known as bone marrow transplant).

Children with AML in the intermediate-risk group have neither low-risk nor high-risk gene changes. About 50-60% of people will be cured. However, the outlook in this type of AML is predicted by how well the cancer responds to the first course of treatment, called induction.

Children that have no measurable disease after induction have a better outlook than those who still have measurable disease.

Children with AML that has adverse or high-risk gene changes are harder to treat. Children with high-risk AML often have survival rates of less than 50%, but survival in high-risk AML varies based on the gene change present and how well the cancer responds to early treatment with chemotherapy.

You should discuss your child’s specific outlook with your child’s cancer treatment team.

APL is a unique type of AML. APL can be standard risk (a white blood cell count less than 10,000 at diagnosis) or high risk (a white blood cell count of 10,000 or more). High-risk APL can be more difficult to treat early on and may have more bleeding at diagnosis, which can be severe. The risk group helps doctors decide what treatment is best.

Overall, APL has a good outlook for children with more than 95% survival with current treatments that are different than those used for treating other forms of AML.

About 95% of CML is diagnosed in the chronic phase which can last for a few years if untreated. In rare cases, CML is first diagnosed in blast crisis phase. CML in blast crisis can have signs and symptoms like acute leukemia, such as ALL or AML and is more difficult to treat than chronic phase CML.

CML blasts that have features of lymphoblasts have a better outlook than CML blasts with myeloid features.

For children with chronic phase CML, a good response to TKI treatment is the most important prognostic factor.

Chronic phase CML that does not respond to TKI treatment is harder to treat, and the outlook is worse than CML that responds well to TKIs. Stem cell transplant is still another treatment option for these children.

Children younger than 2 years of age at diagnosis tend to have a better outlook in JMML.

Children with platelet counts above 33,000 and/or low fetal hemoglobin levels tend to have a better outlook. Fetal hemoglobin is a protein that carries oxygen in some red blood cells in young children.

JMML is most often caused by a change to 1 of the 5 genes in the RAS oncogene pathway. These genes are NF1, NRAS, KRAS, PTPN11, and CBL. JMML with more than 1 gene change has a worse outlook than children with only 1 gene change.

In some cases, the genes are normal but are turned on or off by a process called methylation which changes how genes are expressed. JMML with lower levels of methylation tends to have a better prognosis.

JMML is more common in children with neurofibromatosis type 1, a family cancer syndrome, and Noonan syndrome.

Children with Noonan syndrome are short, may have a broad or webbed neck, and may have heart problems and trouble in school. Some infants with Noonan syndrome develop features of JMML in the blood, but do not meet the criteria for diagnosis. These changes can be watched closely and may resolve without treatment over time.