Parent’s Guide to Leukemia

August 18th, 2013 by Brian Maiorana

In the United States, cancer is the second most common cause of death among children between the ages of 1 and 14 years, surpassed only by accidents. Leukemia is the most common form of childhood cancer.

symptoms-leukemia

Leukemia is cancer of the body’s blood-forming tissues, including the bone marrow and the lymphatic system.  Many types of leukemia exist; some forms of leukemia are more common in children, other forms of leukemia occur mostly in adults.

Nearly 500 kids die every year from leukemia in this country. In 2012 there 47,150 new leukemia cases diagnosed and over 23,000 leukemia deaths, according to Federal government statistics compiled by the National Cancer Institute. Nearly 4,000 of these diagnoses will be in children under 15.

 

 

Two types of leukemia account for most cases in children:

  • ALL-Acute Lymphoblastic Leukemia
  • AML –Acute Myeloid Leukemia
  • (ALL) Lymphoblastic Leukemia (91%  5 year survival rate for children under 15)
  • (AML) Myeloid Leukemia (63% 5 year survival rate for children under 15)
  • (ALL) 2012 total deaths in U.S. -1,440 (1/3 occurring in children under 15)
  • (AML) 2012 total deaths in U.S.  – 10,200 (occurs almost exclusively in adults)
  • An estimated 3,811 children and adolescents younger than 15 years old will be diagnosed with leukemia in the United States in 2011.

ALL accounts for 3 out of 4 cases of leukemia in children.  AML accounts for most of the remaining cases. Most leukemia in children is considered “acute” meaning the cancer is spreading rapidly, while many adults have “chronic” leukemia where the cancer spreads much more slowly.

The good news is that most children survive leukemia today. But even for those families that see their child survive, the fight against leukemia is long, expensive, and very difficult.  So The Children’s Leukemia Fund of America  operating in conjunction with Good Charity, Inc works to provide assistance to these children and their families as they cope with hospital visits and procedures.

History of Leukemia

The word leukemia was coined in 1845 by a young doctor in Berlin, Germany.  A 50 year old cook came to the Berlin hospital complaining of fatigue, nosebleeds, and swelling in her legs and stomach. Four months later she died and an autopsy was done. When physician Rudolph Virchow analyzed her blood under a microscope he was surprised to find the patient had very few red blood cells and an abundance of white or colorless cells; he christened this new blood disorder “leukemia” from the Greek, meaning “white blood”.

Virchow Rudolph Virchow

Scientists eventually figured out that white blood cells are an immune system response to infectious disease and foreign objects in the body, but the abnormal white blood cells being generated by people with leukemia no longer effectively perform their role in destroying infectious diseases in the body.

The excess of abnormal white blood cells observed in a leukemia patient crowds out the creation and functioning of their red blood cells, causing the tiredness and paleness that are classic symptoms of anemia. Leukemia also impairs the creation of blood platelets, which clot blood during an injury, meaning any external bleeding by a leukemia patient becomes potentially life-threatening.

Ten years after Virchow’s (and other independent scientists) initial discoveries, pathologist Ernst Nuemann conducted an autopsy on a leukemia patient where he discovered the patient’s bone marrow was a greenish-yellow color, not the normal red color that human bone marrow should be.  Further scientific exploration of this leukemia patient led to the basic understanding that bone marrow is the source of blood cell generation, a key insight into the function of the human body.

For the next 80 years leukemia was considered scientifically interesting, but still obscure and considered relatively rare. As late as 1930, researchers were still debating whether leukemia was an infectious disease or a type of cancer, but by 1960 leukemia would become a very high profile sickness. Statistics collected in Great Britain during this era ranked leukemia as the second leading cause of death among British children.  Whether the increase in leukemia rates came from better diagnostic techniques or from an actual increase in the real number of leukemia cases caused by changes in the natural environment from industrial and/or other toxins is not clear.

While Leukemia’s importance as a deadly disease became more prominent, there was still not an improved understanding of what caused the disease or how it could be treated. In fact, when leukemia first became more common, researchers were still debating whether it was an infectious disease or a cancer. This lack of understanding of leukemia hampered the development of effective drugs for the disease;  a 1936 analysis found that most children lived only a few weeks after being diagnosed with leukemia.

Leukemia Treatments | Early Years

Not until after WW2 did serious progress begin to occur on treatments for childhood leukemia, and leukemia generally.

The years before World War II had seen the cure of pernicious anemia, a disorder caused by vitamin B-12 deficiency characterized by the creation of excess immature red blood cells in the bone marrow, which was similar to effects observed in leukemia. Another B vitamin, Folate, was used to cure other types of anemia seen during pregnancy and infancy.  A team of researchers in Boston led by Sydney Farber wondered whether folic acid (man-made Folate) would also cure Acute Lymphoblastic Leukemia (ALL) because ALL also featured immature blood cells and anemia.

The initial trials of folic acid were an immediate disappointment;  not only did folic acid not help ALL, it actually seemed to make it worse . It was then reasoned that folic acid may have actually  stimulated the growth of leukemia cells as well as normal cells, so Farber and his research team  instead tried to block that stimulation with another drug. In a major breakthrough, this two-drug combination worked to create temporary remission with the return of normal blood cells and health.  An early victory had been won in the war against childhood leukemia.

The next key breakthrough came from studying the impact of radiation exposure on survivors of the Hiroshima and Nagasaki atomic bombings.hiroshima_survivors

 

It was discovered that the radiation from the bombs damaged the chromosomes (which contain the genes that control our body’s growth and functioning) of people exposed to the nuclear fallout and made them prone to developing leukemia. This suggested that the cause of a cell becoming cancerous lies in the genetic machinery of the cell itself,  a new discovery.

In 1950 Gertrude Elion and George Hitchings, who received the Nobel Prize for their efforts, developed a new drug which was designed to interfere with DNA synthesis and kill rapidly growing cells like leukemia. At about the same time, cortisone-based drugs were new and were tried for virtually every disease, including cancer. These cortisone-based drugs were also found to result in the improvement in the duration and quality of survival for children with ALL.

Unfortunately, these advances proved to be transitory; all of the children treated at this time eventually died because resistance to these drugs eventually developed. Nevertheless, this short term success in treating acute leukemia in children propelled the scientific community into further important research.

Between 1949 and 1954, the first clinical trials that tested combinations of chemotherapy drugs for childhood ALL (Acute Lymphoblastic Leukemia)  were carried out. Patients did live longer with these new combinations of chemotherapy drugs, but all of them still died, usually within a year.

Building on this post-war era research, more and more treatment regimens were developed and studied, and by the early 1970’s, five year survival rates for children with leukemia were up to 50%, a remarkable increase from just 10 years prior.

The 1970’s saw a further increase in survival rates due to better control of infection and bleeding, better nursing, increased Federal research funding, and help from the  public- especially the children and families who participated in numerous clinical trials and studies. Today, 5 year survival rates in children with leukemia are over 90% for ALL and over 60% for AML, a spectacular increase in saved lives!

Leukemia Causes

The precise causes of leukemia is likely different in each patient, and are the result of a complex interaction between genetic factors and different environmental carcinogenic agents, such as ‘in utero’ radiation, child and parent’s exposure to certain industrial chemicals and solvents, or other occupational factors, like paternal exposure to motor vehicle exhaust, hydrocarbons, and paints.

Some people have a genetic predisposition towards developing leukemia. This predisposition is demonstrated by family histories and twin studies. The affected people may have a single gene or multiple genes in common. In some cases, families tend to develop the same kinds of leukemia as other members; in other families, affected people may develop different forms of leukemia or related blood cancers.

Viruses have also been linked to some forms of leukemia. Experiments on mice and other mammals have demonstrated the relevance of viruses in leukemia, and human viruses have also been identified, specifically in adult T-Cell leukemia.

A few rare cases of maternal-fetal transmission (a baby acquiring leukemia because its mother had leukemia during the pregnancy) have been reported.

Children with Down Syndrome have ten times the chance of developing ALL, and 50 times the risk of developing AML.  Down Syndrome is also known as trisomy 21, which is a copying error in the 21st chromosome of human DNA. Several genes on chromosome 21 have also been found to be disrupted in people with leukemia.

The importance of in-utero (while the mother is still pregnant) genetic events has been suspected for many years based on concordance studies on twins with leukemia. An identical twin is twice as likely as the general population to develop leukemia if his or her twin developed the illness before the age of 7 years, but twins who reach age 15 years without developing leukemia do not have at higher risk of developing the disease.

Siblings of children with leukemia are at greater risk of developing leukemia than children whose siblings do not have the disease. Also, a positive family history for cancers of the blood, bone marrow, or lymph nodes among first- or second-degree relatives has been associated with a small increased risk for childhood ALL. So, there is a definite inherent genetic basis for leukemia.

Some cancers have been shown to have viral origins. A viral origin for leukemia is evinced by two observations:  first, the peak incidence of childhood leukemia and that of common childhood infections both occur among children 2–5 years of age, the age group least likely to possess sophisticated immune systems.

Some studies have also shown evidence of seasonal variation in the birth or onset dates of childhood leukemia, which could point to some virus or bacteria whose presence in the natural environment varies with climate.  Other studies have shown no evidence of seasonality.

 Population Mixing Theory of Childhood Leukemia

Another, somewhat odd, finding: an excess of childhood leukemia has been found in rural populations that have undergone an influx of new residents; this theory is known as population mixing.  This theory proposes that an infectious agent coming into a previously unexposed community, like a remote rural area, might cause an epidemic of ALL. Susceptible individuals may be exposed to infectious agents brought into the area by new residents, triggering their genes to  start creating cancerous cells.

Delayed Infection Theory of Childhood Leukemia

Another theory is the mechanism of “delayed infection”. This idea grew out of the observation that children with ALL have been seen to be less likely to have had common infections during their first few years, perhaps suggesting immunologic isolation early in life. In other words, children who have not been exposed to the full rigors of the natural environment may not develop the immune system to protect them from the “catching” leukemia.

Both the Population Mixing Theory and the Delayed Infection Theory imply that leukemia is/can be caused by a virus or bacteria. While there is certainly some evidence this is possible, it is far from conclusive and neither of these alternative theories would explain the full range of childhood leukemia.

Environmental Factors

  • Maternal marijuana use before and during pregnancy has been associated with childhood AML and ALL. Findings from a Children’s Cancer Group study showed a 10-fold risk increase of childhood AML associated with maternal use of marijuana just before or during pregnancy. The authors concluded that, because marijuana has been shown to interfere with fetus development in some animals and possibly humans, it may cause leukemia to form in utero.
  • In one large study, fathers who had long term exposure to certain plastics during the preconception period had an abnormally frequent amount of children that developed leukemia, though this result  was not considered statistically significant.
  • In a 2010 study by the University of California, Berkeley’s School of Public Health, researchers found that children with acute lymphoid leukemia (ALL) had almost twice the chance of having been exposed to three or more X-rays compared with children who did not have leukemia.
  • Mothers of children with leukemia more frequently worked in the metal manufacturing /processing industry, the textile industry, or as a pharmacist.
  • A recent study in Great Britain found association between birthplace of children with leukemia and proximity to industrial sites that release volatile organic compounds including dioxins, one of the so-called “dirty dozen” of dangerous chemicals found to be persistent organic pollutants. More than 90% of human exposure is through food, mainly meat and dairy products, fish and shellfish.
  • Specific occupations found more frequently among mothers of children with leukemia include metal manufacturing or processing, textiles, and pharmacist.
  • Maternal alcohol consumption associated with AML, Paternal alcohol consumption NOT associated with increased risk.
  • It is unclear whether maternal or paternal cigarette smoking before or during pregnancy is a risk factor for developing childhood leukemia. Two studies found that the frequency, amount, and duration of paternal smoking before conception were related to significantly elevated risk; a later study adjusted for maternal cigarette smoking found no impact from paternal smoking.

Despite many advances in the treatment of childhood leukemia and a drastic increase in survival rates for leukemia patients,  the causative factors of Acute Lymphoblastic Leukemia (ALL) and Acute Myeloid Leukemia (AML) remain unclear. Identifying environmental, genetic, and infectious risk factors is the key next step in fighting leukemia. While evidence does exist for a wide range of potential causes for leukemia, much of that evidence is weak or inconsistent. For now, exposure to ionizing radiation is the one environmental exposure strongly factor conclusively shown to increase risk for the development of leukemia in children.

Information on the many of the studies cited above can be found  here and here.

 Leukemia: Current research and treatments

Additional drugs and improvements in supportive therapy also helped bring the cure rate of childhood ALL up to its present high rates. But even when radiation and drug therapy cures children of leukemia, the treatment is so toxic that it can cause a number of serious complications, including the development of a new type of leukemia or brain tumors or heart problems. Part of the toxic nature of the therapy resides in the fact that it is not specific—it doesn’t affect just leukemia cells, but healthy cells also.

Tyrosine Kinase Inhibitor Drugs

Tyrosine kinase’s are enzymes that can turn certain function “on” or “off”.  These enzymes have been implicated as playing key roles in the development of various types of human cancers, including leukemia, breast and bladder cancer. Consequently, tyrosine kinases have become hot new targets for anticancer drugs; one of the most effective of these inhibitors is Imatinib; marketed under the brand name Gleevec, Imatinib has been cited as the first of the exceptionally expensive cancer drugs, costing $92,000 a year. Doctors and patients complain that this is excessive, given that its development costs have been recovered many times over, and that the costs of synthesizing the drug is a very small fraction of the sale price.

 Leukemia Treatment Difficulties:

While most childhood leukemia patients suffer from ALL or AML, some patients have leukemia sub-types that are resistant to chemotherapy. In these cases the more drastic measure of performing bone marrow transplants is necessary, as this risky procedure is their only hope for a cure. In contrast, a few sub-types of leukemia easily succumb to chemotherapy in children, and require less than the standard 2-3 year chemotherapy regimen.

When to stop standard chemotherapy is actually one of the more thorny decisions doctors have to make when treating leukemia patients. The various chemotherapy drugs are highly toxic to the body and subject their patients to life-threatening side effects, so ending treatment as soon as possible is necessary; but if chemotherapy is stopped too soon, the leukemia could return in an even more aggressive state.

Some evidence for difference in treatment effectiveness between African-American and Caucasian children has been observed, though it is not yet known if this is due to some genetic difference or differences in the access to health care and variance in the adherence to treatment regimens  between African-American and Caucasian patients and their families.

 

leukimia

The Children’s Leukemia of America Fund is committed to supporting children with leukemia and their parents during the long and arduous process of fighting the disease.  

 

 

 

 

The Future of Leukemia treatment: Precision Medicine

“Precision Medicine” is an umbrella term for the various new medical treatments being implemented or on the verge of being implemented made possible by the exponential increase in computing power occurring every year.  The human genome being sequenced and the development of nanotechnology, which allows manipulation of chemicals and human tissues at the molecular level, are opening new vistas of possible treatments for all diseases, including leukemia.

Not just new technology, but the collection of data about patients, treatments, and disease is at the heart of “Precision Medicine”, and the academic and research communities are turning much of their attention to these new technologies. For example, www.MeForYou.org is an outreach effort by the University to recruit patients into the data web that is used to implement and refine Precision Medicine techniques.

http://www.youtube.com/watch?v=hfBjFUfwg9U

MeForYou  defines its mission and work in this way:

“Precision medicine cannot work without the contributions of individuals who want their own health information (including genetics, blood test results, responses to medications and reactions to therapies) to someday inform a global knowledge network that can better connect innovative research to patient care.”

Precision Medicine Symposium at University of California-San Francisco.

Brian Maiorana,director of the Children’s Leukemia of America Fund and Good Charity, Inc, recently visited the University of Michigan’s Children’s hospital to make a financial contribution to a cutting-edge “Precision Medicine” research program.  Researchers there at C.S. Mott Children’s hospital are actually mapping the full blueprint (this process is known as “sequencing”) the DNA/RNA of a patient’s cancerous cells, comparing it to the genomic profile of their non-cancerous cells, and creating a unique and individual treatment plan specifically for that patient. As the doctors mention in their interview, this has already saved the lives of several children in the study. yhttp://www.youtube.com/watch?v=XE5o2OZhV78

The work being done by the UM Precision Medicine team working specifically on childhood leukemia is predicated on the realization that the treatment  of cancer is not a “one size fits all” approach. Discriminating molecular subsets of cancer based on genetic biomarkers is essential to the development and application of precision cancer medicine.

The University of Michigan researchers hypothesize that sequencing the cancerous cells of pediatric cancer patients in real-time will translate to more effective treatment.  While there are other centers doing genomic analysis of pediatric tumors, no one except the Michigan team are doing these analyses in a real-time fashion. In the first round of real-time sequencing, the team has found treatment changing biologic information in about one out of three patients sequenced among the first 15 patients enrolled, including one potentially lifesaving breakthrough .

The human genome was first sequenced by (around) 2001 at a cost of roughly 3 billion dollars. Today, the cost to sequence the DNA of a patient in the UM “Precision Medicine” program has come down to about $10,000.  and Children’s Leukemia of America Fund director Brian Maiorana was proud to present the UM “Precision Medicine” research team with a check for $10,000, enabling the DNA sequencing and treatment of another child with leukemia.

Precision medicine has the potential to deliver some of the most significant changes on the healthcare horizon: improving diagnosis, treatment and patient prognosis. The arrival of precision medicine is imminent.

 Conclusions

In the space of 150 years, leukemia has been identified, studied, and controlled to some extent. But the fight is far from over, hundreds of children and thousands of adults still die every year from leukemia, and the financial, physical, and emotional toll on the survivors and their families is immeasurable.  The drive to fully understand and neutralize leukemia must continue until the disease has been totally eradicated; financial support for new treatment regimens as well as for current victims of the disorder must continue to grow and expand.  The Children’s Leukemia Fund of America is dedicated to just that cause.

 

 

 

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