Acute Promyelocytic Leukemia Treatment Innovations
By Dhenu Ruhlin April 28, 2004

[Mrs. Ruhlin wrote this report for her MBA class at Rice University.  Her husband was diagnosed with APL and was undergoing therapy at the same time--Dr. Koller]

Executive Summary
The purpose of this paper is to examine successful innovations in leukemia treatments.  This paper will discuss the background of leukemia and history of leukemia treatments, concentrating primarily on Acute Promyelocytic Leukemia (APL) – the type that my husband was diagnosed with in January of this year – and the sources of innovation for these treatments. 

Treatment innovations in the medical field, primarily driven by the researchers and doctors, are developed for the sole purpose of finding cures for any given disease.  Some of these treatments can be considered ground breaking or even radical; however, once the survival and remission rates increase and surpass any current treatment, these “radical” treatments become the “dominant design” utilized by doctors and hospitals.

In class, we defined a “successful innovation” as “one that returns more than the original investment.”   In writing this paper, I truly believe that innovations in APL treatments are very successful because, today, they do return more than the original investment.  In this case, I would define the “original investment” as the time and effort taken to develop the latest innovative treatment, all-trans-retinoic acid (ATRA) combined with arsenic trioxide therapy (ATO).  I would further define the “return” as the high success rate in achieving complete molecular remission (CR) with minimal physical side effects and the ability to maintain most normal activities with a disease that is considered the most devastating subtype of leukemia.  Success in this treatment is also directly linked to fact that we are battling leukemia in the Year 2004 and have the available resources, the doctors and nurses of M. D. Anderson Cancer Center, with whom we have been able to come as far as we have and will continue in the future.

Background
Blood is composed of a mixture of plasma and cells. The plasma is composed of water, which includes dissolved proteins, hormones, minerals, vitamins, and antibodies.  The cells include red blood cells, platelets, neutrophils, monocytes, eosinophils, basophils, and lymphocytes.  Red blood cells make up half of the volume of blood and are the primary mode of transportation of oxygen throughout the body.  Platelets, one-tenth the size of red blood cells, help stop bleeding by clotting any torn surfaces of blood vessels.  Finally, neutrophils, monocytes, eosinophils, basophils, and lymphocytes, collectively the white blood cells, have the ability to combat infections, ingest bacteria or fungi, and kill them.  The marrow, the central cavity of the bone, is where normal and healthy blood cell development takes place.  When the cells are fully formed, they enter the blood stream.

Leukemia, the cancer of the blood and the bone marrow, is most commonly associated with abnormal white blood cell production.  Each year approximately 27,000 adults and more than 2,000 children in the United States learn they have some form of leukemia.   Leukemia is divided into four categories:  myelogenous and lymphocytic, each having an acute (sudden onset) and chronic (long-lasting) form, where myelogenous and lymphocytic denotes the distinct cell type involved.  

Causes of Leukemia
The specific cause of leukemia is still unknown to the medical field.  Researchers believe that viral, genetic, environmental, or immunologic factors may potentially be involved.  Some viruses have caused leukemia in animals; however, researchers believe that viruses cause only very rare types leukemia in humans.  They also believe that there may be a genetic predisposition to leukemia in some patients.  Environmental factors, such as exposure to certain toxic chemicals or excessive radiation, have been linked to the development of leukemia; however, these links are only prevalent in extreme cases.  Finally, people with immune-system deficiencies have a higher risk for cancer since the body’s ability to fight foreign cells is decreased.  Even with all these factors, scientists still have not determined any one specific cause of leukemia.

Identification of Leukemia
In diagnosing the specific type of leukemia, doctors utilize results from both blood and bone marrow tests.  There are two specific bone marrow tests:  bone marrow aspiration and bone marrow biopsy.  In the aspiration procedure, a sample of the bone marrow cells is removed from the hip bone; where as in the biopsy procedure, a small piece of bone is removed.  Based on these tests, doctors evaluate specific chromosomes and their appearance, specific features on the bone marrow cell surface, and the appearance of the bone marrow cells under a microscope.   Once the type of leukemia is identified, patients undergo treatments that are specific to that type of cancer.

Acute Promyelocytic Leukemia (APL)
Within Acute Myelogenous Leukemia (AML), there are eight subtypes, including Acute Promyelocytic Leukemia (APL).  Currently, APL, diagnosed primarily in young adults and documented as a subset of AML in 1957, accounts for 5% - 10% of all AML cases.   APL is caused by the genetic exchange of material in chromosomes 15 and 17, also known as t(15;17) translocation.  The translocation is a “defect that fuses the promyelocytic leukemia (PML) gene on chromosome 15 with the retinoic acid receptor alpha (RARa) gene from chromosome 17.  The presence of the PML-RARa can be used to diagnose and monitor therapeutic efficacy in patients with APL.”  

Researchers have not determined the direct cause of this mutation; however, they believe due to the newly formed PML-RARa protein, the neutrophils are unable to undergo their normal five-stage production cycle and are blocked in the immature second stage, Promyelocytic Stage.   As the promyelocytes (immature neutrophils) are produced in abnormal amounts, the bone marrow loses the ability to produce the remaining cells, including red blood cells and platelets.   The typical symptoms of APL consists of fatigue, minor infections, tendency to bleed under the skin or from the gums, internal hemorrhage in the brain or other organs, abnormally low levels of platelets, and sever bruising.  Due to these symptoms, APL has historically been considered one of the most devastating subtypes of AML, with a non-treatment survival rate of approximately 3- 6 months.

Acute Promyelocytic Leukemia Treatments
Since APL cases were first documented in the 1950’s, treatments for this devastating form of cancer have seen significant advancements.  APL treatments can be classified into two eras:  Pre -arsenic Trioxide (1950’s to 1990’s) and Arsenic Trioxide (1990’s to Present).

Pre-arsenic Trioxide Era
Traditionally, as with all cancers, cytotoxic chemotherapy was the preferred treatment for APL.  Cytotoxic chemotherapy not only kills cancerous cells, but also normal cells, particularly in the bone marrow; the rational being that normal cells would more likely survive the effects of the drugs than the cancerous cells.   However, utilizing the traditional cytotoxic chemotherapy treatment alone proved to be very unsuccessful in APL patients.   In the early 1970’s to late 1980’s researchers utilized Anthracycline-based chemotherapy, utilized for breast cancer patients, along with management of coagulopathy, which allowed for improved blood clotting.  This advancement in the treatment yielded remission rates of 50% - 80% in patients with APL.  

By the late 1980’s medical researchers in China noticed that most cancer patients showed lower levels on natural vitamin A (retinal) in their blood.  Chinese researchers also found that those using a traditional Chinese herb called “xiao chai hu tang” had vitamin A levels closer to normal and had higher cancer survival rates.   At the same time, they realized that during the t(15;17) translocation, exhibited in all APL patients, the retinoid receptor RAR is deactivated.  Based on this knowledge, Chinese researchers developed a vitamin A derivative, all-trans-retinoic acid (ATRA), that would activate the retinoid receptor and cause the immature promyelocytes to mature.   

Because of this discovery in China and subsequent FDA approval of ATRA, doctors began to utilize ATRA to treat APL patients from the late 1980’s to roughly 2001.  The remission rates increased in some; however, researchers also determined that ATRA alone did not produce complete remission.  They found that as the promyelocytes matured, the white blood cell count increased; however, the absolute neutrophil count, the good white bloods cells, did not increase.  For this reason, doctors began utilizing ATRA in combination with traditional Anthracycline-based chemotherapy to kill the matured promyelocytes and allow the neutrophils to grow.   This combination allowed for slightly higher rates of complete remissions; however, the chemotherapy still had severe side effects, such as fatigue, vomiting, and hair loss.

Arsenic Trioxide Era
“APL, once considered the most devastating subtype of AML, is now the most treatable of all subtypes as a result of intensive research into its molecular pathogenesis.”   This statement was made possible, once again, due to a discovery made in China in early 1970’s.

Arsenic, a common, naturally occurring substance, has been used therapeutically for more than 2,400 years.  Arsenic’s antileukemic activity was first reported in the late 1800’s; it was reported to reduce the white blood cell count in two normal people and one patient with “leucocythemia.”   In the United States, as early as 1960’s, arsenic therapy was tested and proved to be effective in animals with tumors; however, despite these observations, arsenic was replaced with other anticancer drugs in the early 1970’s, due to concerns about its toxicity and the potential for skin cancer.   Researchers in China, however, as early as the 1970’s were successfully utilizing controlled doses of arsenic therapy for treating APL.  It was not until 1996, when the first scientific reports were written by Chinese researchers detailing the effects of the arsenic therapy for APL treatment, did the United States consider arsenic as a viable treatment option.   By September 2000, the FDA approved intravenous injections of controlled doses of arsenic for the treatment of APL. 

The documented benefits of this innovative treatment have led many US doctors and hospitals to utilize arsenic trioxide as a front-line treatment for APL.  Since its approval, arsenic trioxide, along with ATRA, has been the standard treatment for APL.  Although arsenic trioxide is still considered a form of chemotherapy, the side effects are minimal compared to those experienced when undergoing traditional chemotherapy.  The patient does not experience severe fatigue, vomiting, or hair loss.  Currently, the long-term effects of arsenic are still unknown; however, the benefits (achieving remission at the molecular level not just at the blood level) outweigh the risks. 
Sources of Innovation
Innovation, as defined in class, is “the mobilization of knowledge and technical skills and experience to create new products, processes, and services.”   Applied Research is “focused on solving specific technical problems or opportunities” and Development is “the creation of new products, services, or processes at the proto-type or market demonstration level.”  

In the case of APL treatments, the innovations began with the researchers and doctors in the field.  The progression of treatment innovations or advancements was mainly driven by their quest for finding a cure for leukemia. Based on the history of APL treatments advancements, it is clear that researchers and doctors utilized their knowledge and skills to create new products as new obstacles become apparent.

In one of our many conversations with our doctor, I asked Dr. Koller why he chose to treat leukemia patients, what drove leukemia treatment innovations, and who drove these innovations.  His response was plain and simple. “Of all the cancers, the most lucrative one is Lung Cancer because of the number of people who voluntarily smoke and eventually develop cancer.”  He, however, chose to treat leukemia patients because he believes that “leukemia patients are innocent victims, who have done nothing wrong to develop this disease.  Leukemia can develop in all ages, races, and genders.”  Innovation in this field truly begins with the researchers and doctors who have the passion and have devoted their time and effort in finding cures to help their patients. “Most of the innovations occur as patients develop new forms of the disease.  Sometimes the researchers are the right place at the right time – it can be pure luck!”  

Over the years, treatments have advanced mainly because of the applied research and development.  As research advanced, the benefits for APL patients have also increased.  Although APL is still and will always be a very serious disease, what was once considered the most debilitating subtypes of AML if untreated, now has the most advanced treatments, with the highest complete molecular remission rate.  Today, researchers and doctors have brought APL treatments to the forefront.  By utilizing ATRA in conjunction with ATO as the standard treatment option, the quality and length of life for APL patients has been increased.

Future Innovations
The current APL treatment is at its most innovative position.  However, M. D. Anderson Cancer Center is conducting ongoing research to measure “the effects of the drugs on the abnormal cells and to see if measures that are more sensitive can be developed to predict relapse and toxicity.  The latest study is designed to understand how genes may explain the different responses people have to the same drug.  The goal of this research is to find genetic markers that will identify persons with APL who will have the best possible response to ATRA and Arsenic or to identify persons who will have fewer side effects in order to maximize their benefit from the combination.”   As with any medical innovation, on going applied research is critical in developing cures for diseases, which will eventually help many future patients.  When my husband was diagnosed, we consented to be part of this ongoing research, which allowed us, in a small way, to give back to a field that has provided us with tremendous hope and support in battling this grave illness.