Leukemia Symptoms & Lessons: Is A Solution In Sight?
1. What is Leukemia? A Definition Of Leukemia, The Most Common Blood Cancer
Leukemia is a cancer of the blood cells that starts in the bone marrow - the soft center in the middle of bone where blood cells are formed. It affects 10 times more adults than children, more commonly people over the age of 50.
Bone marrow makes three types of blood cells:
- white blood cells (leukocytes) that fight infection and disease
- red blood cells (erythrocytes) that carry oxygen throughout the body
- and platelets that form blood clots to help control bleeding.
Leukemia is the term used to describe cancers that affect white blood cells.
2. Types Of Leukemia
People with leukemia produce abnormal white blood cells that, initially, function normally. However, leukemia cells don't die when they become old or damaged, and because leukemia cells are constantly dividing to make copies of themselves, eventually they build up and crowd out normal blood cells. Levels of normal blood cells get very low making it hard for the body to supply oxygen to tissues, control bleeding or fight infection.
The four most common types of leukemia are:
- chronic myeloid leukemia (CML)
- acute lymphocytic leukemia (also called acute lymphoblastic leukemia) (ALL)
- acute myeloid leukemia (AML)
- chronic lymphocytic leukemia (CLL) - the most common of all leukemias.
Chronic means that the leukemia gets worse over time. Acute means that the leukemia gets worse quickly.
CLL, CML, and AML are diagnosed more in adults. ALL is more common in children.
3. Leukemia Symptoms
There are so many different types of leukemia that there is no one symptom that suggests you have leukemia. Symptoms generally reflect problems related to having a low blood count and may include:
- Dizziness or feeling lightheaded
- Easy bruising or frequent or severe bleeding from the nose or gums
- Loss of appetite
- Night sweats
- Shortness of breath
- Recurring or persistent infections
- Tiredness or fatigue
- Weight loss.
- Abdominal swelling, bone or joint pain
- A feeling of fullness soon after eating a meal
- Enlarged lymph nodes
- Swelling of the thymus.
It is important to note that many of theses symptoms are more likely to be caused by something other than leukemia. A blood test is the only way to tell. In 2017, the FDA approved ClearLLab Reagents (T1, T2, B1, B2, M); the first test to help detect certain leukemias and lymphomas.
4. Research Into The Cause Of Leukemia
In order to find an effective treatment for a disease, first you have to try and understand what causes the condition in the first place.
Great progress has already been made by scientists with regard to understanding DNA changes that cause the production of leukemic cells. But as they dig deeper, researchers have realized that there are more different types of leukemia than first thought.
One of the most common types of DNA change that can lead to leukemia is a translocational change. Our DNA is packaged into 23 pairs of chromosomes. If a part of the DNA from one chromosome breaks off and attaches itself to another chromosome it can affect how certain cells in our body behave.
For example, the most common translocation in CML and ALL is the Philadelphia chromosome, representing a swap in DNA between chromosomes 9 and 22. This abnormality occurs in 90-95% of patients with CML and 1 in 4 adults with ALL.
For CLL, the most common change is a deletion, or loss, of part of a chromosome. In most patients with CLL, the deletion is found on chromosome 13, but other chromosomes such as 11 and 17 can also be affected. In some patients with CLL, there is an extra chromosome 12.
Scientists are still mapping chromosome changes with different types of leukemia. But one thing is certain, not everybody fits into the same square box!
5. Genes And Leukemia: The Philadelphia Chromosome
The discovery of the Philadelphia chromosome in 1960 provided the first proof of a genetic link to cancer. Peter C. Nowell and David Hungerford identified the presence of an unusual, small chromosome in cancerous cells of patients with chronic myelogenous leukemia (CML). Normal leukocytes in these same patients lacked this abnormality.
With advances in technology, subsequent research was able to identify that the abnormal chromosome was the result of a reciprocal translocation between the long arms of chromosomes 9 and 22, that resulted in expression of a fusion protein named BCR-ABL in malignant cells. 90-95% of patients with CML are found to have this abnormality; however, it is not specific to CML as it is also found in some patients with ALL and occasionally in AML.
Elimination of the Philadelphia chromosome in patients who have Philadelphia-positive leukemia is deemed necessary for a cure.
6. Leukemia Treatment: How The Philadelphia Chromosome Influenced Treatment
Treatment for leukemia usually needs to start as soon as possible after diagnosis, because many forms of leukemia progress very quickly.
Chemotherapy has always been the main form of treatment. Traditional chemotherapy drugs like cytarabine and daunorubicin kill rapidly dividing cells. Unfortunately, these drugs cannot tell the difference between cancerous and normal cells, resulting in the death of many healthy cells and side effects such as stomach problems (nausea, vomiting, and diarrhea), hair loss, low blood counts, and mouth sores.
These type of treatment options are far from perfect, so discoveries such as the Philadelphia chromosome allow for more targeted type treatments. Researchers are unwavering in their aim for a cure for cancer and the more they know about what causes a disease, the better able they are to treat it. Survival rates have dramatically increased for most types of leukemia since the 1960s, although prognosis remains better in younger people compared with seniors. Sixty years ago, only one in ten children survived childhood leukemia. Now, eight in ten do. With adult leukemia, around 50% survive for five years after diagnosis. Scientists believe we can still do better than that.
7. Imatinib: Gleevec Was The First TKI Against CML
Imatinib (Gleevec) changed the way leukemia was treated forever. Imatinib belongs to a group of drugs known as tyrosine kinase inhibitors (TKI), and was first approved by the FDA in 2001 to treat Philadelphia chromosome-positive CML.
Imatinib targets a specific type of protein (BCR-ABL) that only exists in cancer cells. As a result, the cancerous cells stop growing and eventually die, while healthy cells remain unaffected.
Dasatinib (Sprycel - FDA approved 2006), a second generation TKI, was created to overcome the problem of intolerance or resistance to imatinib. Dasatinib inhibits the BCR-ABL protein at 325 times the potency of imatinib and is effective against almost all mutations of the Philadelphia chromosome, except one (the T315I mutation).
Many other TKIs have since been developed including nilotinib (Tasigna [FDA approved 2007]), bosutinib (Bosulif [FDA approved 2012]), and ponatinib (Iclusig [FDA approved 2012]); all improve on imatinib and are recommended to be used with other forms of standard chemotherapy. For example, ponatinib is the only TKI that can work against T315I mutant cells, although several other new TKIs aimed at this mutation are in the pipeline. TKIs are also used to treat several other types of cancers including Philadelphia chromosome-positive Acute Lymphocytic Leukemia (ALL).
8. Targeting A Specific Mutation: Omacetaxine (Synribo) For CML
There is a subgroup of patients with CML that fail to benefit from TKIs.
Omacetaxine (Synribo) is a protein synthesis inhibitor and is approved for adults with CML in the chronic or accelerated phase of the disease who have already tried at least two TKIs without success. Omacetaxine inhibits protein synthesis and targets proteins responsible for the proliferation and survival of leukemic cells, causing cell death.
Omacetaxine is effective even in patients with the BCR-ABL T315I mutation - this mutation confers resistance to the TKI inhibitors bosutinib, dasatinib, imatinib, and nilotinib. Hematologic side effects (such as thrombocytopenia [low platelets], anemia and neutropenia [low neutrophils]) occur in approximately three quarters of all patients prescribed omacetaxine. Other common side effects include infection, diarrhea, fever, tiredness, lack of energy and nausea.
9. Leukemia Treatment: Combination Treatment And Development Of A Cancer Vaccine
For CML, the combination of imatinib with other chemotherapeutic agents and drugs that target the BCR-ABL protein has proven very effective; however, not everyone experiences the same response.
Researchers are now looking at whether certain combinations of medicines are better than others, and the effect of new cancer vaccines currently in development.
Several new drugs for leukemia are currently undergoing phase 2 or 3 testing and there is hope that these will improve future treatment outcomes.
10. Acute Lymphocytic Leukemia Treatment
Treatments for adult acute lymphocytic leukemia (ALL) include chemotherapy, targeted therapy and stem cell transplantation. Since ALL is technically a group of related diseases and not a single disease, treatment varies depending on the different subtype, response to treatment and outlook.
Treatment typically lasts for 2 years, with the first few months involving more intensive type treatment. Experts are also looking at different combinations of treatments in an effort to improve response and reduce side effects.
Agents such as clofarabine (Clolar) appear more effective at treating childhood ALL, although trials are currently looking at their effectiveness in adults. The optimal length of therapy is also a subject of debate in people with a good prognosis. Experts are also not sure if more intensive chemotherapy benefits those with a worse initial outlook.
As with CML, the effectiveness of chemotherapy can sometimes be limited because leukemia cells become resistant to it. Finding ways to prevent or reverse this resistance is also high on the agenda.
11. Marqibo For ALL: Transforming Vincristine
Vincristine has been used to treat cancer for almost 50 years. However, it can be tricky to use and can cause nerve toxicity which limits its dosage and how long it can be given for.
Marqibo is a specially-formulated type of vincristine that was approved for patients with Philadelphia chromosome-negative ALL in 2012. Marqibo uses liposome technology to transport vincristine to where it is needed most, overcoming any problems with absorption of the drug and restricting its spread to other parts of the body.
12. The March Of The Monoclonal Antibodies Against ALL
Several drugs that stimulate the immune system rather than directly kill cancer cells have recently become available, or soon will be marketed, as a treatment for ALL.
Examples include the monoclonal antibody, blinatumomab (Blincyto). Blincyto directs immune T-cells to bind to specific proteins (such as CD19) on the surface of leukemic cells and is approved for a specific type of ALL known as Philadelphia chromosome-negative B-precursor ALL. This medicine is given after other cancer treatments have failed.
Besponsa (inotuzumab ozogamicin) is another example. This antibody-drug conjugate (a CD22 monoclonal antibody linked to a chemotherapy drug) was approved in August 2017, filling a void in treatment for people with relapsed or refractory CD22-positive B-cell precursor ALL (Philadephia chromosome-positive or negative) that have failed treatment with at least one TKI. This type of ALL is typically fatal within months. Besponsa attaches directly to B-cell ALL cancer cells that express the CD22 protein and delivers the potent toxin, ozogamicin, into those cells.
13. Chimeric Antigen Receptor Therapy: A New Stage Is Set
Scientists made a breakthrough when they discovered it was possible to individually re-engineer immune system T-cells to recognize specific proteins on cancer cells. The re-engineered T-cells are known as Chimeric Antigen Receptor (CAR) T-cells, and once multiplied and infused directly back into a patient, they have the ability to recognize, attack and kill cancerous cells containing that specific protein on their surface.
Two CAR T-cell products are approaching market. Novartis is trialing CTL019 (currently named tisagenlecleucel-T), for relapsed and refractory ALL in pediatric patients, with impressive results an 82% complete remission rate in the ELIANA tria).
Kite Pharma, Inc., began a rolling submission for FDA approval for their product, called KTE-C19 (axicabtagene ciloleucel) in December, 2016. Their trial results have also been impressive, with some response rates reportedly 6-fold higher than historical outcomes. KTE-C19 received a Breakthrough Therapy Designation (BTD) by the FDA in late 2015 for certain types of lymphoma, including diffuse large B-cell lymphoma (DLBCL). High complete remission rates in ALL have also been reported.
15. Advances In Testing Detect Even Tiny Amounts Of Residual Leukemic Cells
Scientists know that one leukemic cell has the potential to divide into thousands of other leukemic cells, so treatment aims to rid the body of EVERY leukemic cell possible. But routine bone marrow tests are just not sensitive enough to pick up small amounts of leukemia cells.
Luckily, the highly sensitive tests used to detect DNA changes in leukemic patients are just as useful for detecting the smallest amount of leukemia left after treatment. Polymerase Chain Reaction (PCR) tests can detect tiny amounts of leukemia cells left based on their chromosome translocations or rearrangements.
This can help doctors decide whether to continue, stop, or add to treatment.
14. Stem Cell Transplants - Refining To Increase Effectiveness
Stem Cell transplants still offer the best hope of a disease cure. Stem cells are either collected from the person with leukemia or another source before powerful chemotherapy (and sometimes radiation therapy) is used to kill all cancerous cells in their body. Stem cells are then reintroduced via a vein and make their way to the bone marrow where they grow, multiply, and help make healthy blood cells again. But stem cell transplants are not without their risks and some may be fatal.
Experts are keen to improve the effectiveness of stem cell transplants and to reduce the risk of complications. By better identifying patients who are more likely to benefit from stem cell transplants and refining collection techniques, success rates should be improved.
Another technique, called donor leukocyte infusion, attempts to reverse symptoms of relapse in a person who has previously had a stem cell transplant with another person's stem cells. White blood cells (leukocytes) are taken from the same person providing the stem cells and infused into the patient in an effort to boost their immune system. Early results have been promising.
16. AML - One Type Of Treatment Definitely Does Not Suit All
As with most other leukemias, AML is not a single disease, but rather a group of related diseases. Treatment may consist of leukapheresis (the removal of high numbers of leukemic cells from the blood), chemotherapy, stem cell transplantation, or other drugs depending on the subtype or patient's prognosis. Because the disease can progress rapidly, treatment needs to be started immediately.
A specific subtype of AML called acute promyelocytic leukemia (APL or AML M3) needs extra careful management. If regular chemotherapy drugs are used in patients with APL, blood may clot in an out-of-control way. Before this was known, patients sometimes died from treatment.
17. AML Treatment: Tailored To The Patient
Before deciding on the best treatment for AML, doctors take into consideration the age and health of the patient. Patients under the age of 60 are usually given more intensive treatment.
Induction usually involves cytarabine and an anthracycline such as daunorubicin or idarubicin. Sometimes cladribine is given as well. The fixed combination drug, Vyxeos (cytarabine and daunorubicin), was approved in August 2017 and may be given to patients with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Most initial chemotherapy regimens are given in hospital over the course of a week.
Midostaurin (Rydapt) may be considered in people with AML whose leukemic cells have an FLT3 gene mutation. Rydapt is an oral, multi-targeted kinase inhibitor that is taken twice daily and was FDA approved in 2017. Enasidenib (Idhifa) came onto the market in August 2017 for patients with relapsed or refractory AML with an isocitrate dehydrogenase 2 mutation; filling a significant void in treatment for people with this form of AML.
18. Chronic Lymphocytic Leukemia Treatment
CLL is a bone marrow disease that usually gets worse SLOWLY. Because of this, treatment options include watchful waiting, radiation therapy, chemotherapy, surgery, and targeted therapy. Despite improvements in treatment over the last 15 years, significant improvements in the survival of patients with CLL have not been confirmed.
Dozens of new drugs are currently being investigated for CLL, including new targeted treatments, monoclonal antibodies, biologics, immunotoxins, and chimeric antigen receptor (CAR) T-cell therapy. Several other agents, already in use fighting other forms of cancer, are undergoing testing for effectiveness for CLL. Ibrutinib (Imbruvica) and venetoclax (Venclexta) were both approved in 2016 for CLL treatment, being particularly effective in patients with the 17p chromosome deletion.
19.Immune System Boosting: Biologics
The treatment of cancer has been enhanced by biologics, such as monoclonal antibodies (MABS), that teach our body to fight it's own war against cancerous cells. MABS are also used to reduce some of the side effects associated with cancer treatments.
Types of MABS used in the treatment of CLL include rituximab (Rituxan) and alemtuzumab (Campath). These MABS recognize the leukemic cell and coat its surface, triggering destruction by the immune system.
Ofatumumab (Arzerra) is a different type of MAB that works by targeting the CD20 protein found on the surface of CLL cells. This allows the immune system to recognize the marked cells and destroy them. Obinutuzumab (Gazyva) works in a similar way and is used in combination with chlorambucil.
Side effects experienced with MABS are relatively mild and include flu-like symptoms, nausea, headache, fatigue, and sometimes wheezing. Side effects generally last for no more than a few hours post treatment, although some patients may develop an allergic type reaction that can be treated with antihistamines.
20. New Cancer Treatments On The Horizon
Advances in technology and genetic profiling have opened up several new avenues for treatment. Many new drugs in development or at advanced stages of testing aim to beat leukemia in a totally unique way. Examples include:
- Sapacitabine: directly targets DNA synthesis and introduces breaks in the DNA helix, halting replication
- Laromustine: affects the protein guanine on the DNA strand, producing cross-links that lead to cell death
- Tipifarnib and lonafarnib: inhibit protein modification.
Another drug worth mentioning is inotuzumab ozogamicin. Inotuzumab ozogamicin is an investigational therapy that was granted breakthrough status in 2015 for ALL. It consists of an antibody/cytotoxic conjugate that targets an antigen present on 90% of B-cell malignancies. Once bound, the complex releases the cytotoxic agent, calicheamicin.
21. Finding A Cancer Cure: Where To From Here?
In the past, you could say that, in order to understand things better, we have oversimplified many medical conditions. Unfortunately, diseases are never that simple, and in fact, many cancers that we have lumped together are more than likely different types of cancers with similar symptoms.
Luckily, technology has advanced so much it is now possible for scientists to interpret very complicated data. Gene expression profiling is a new laboratory technique that looks at the patterns of many different genes in cancer cells at the same time.
Eventually, this technique may allow for much more personalized treatment by matching gene cluster abnormalities with specific chemotherapy treatments, improving effectiveness. Technology such as this also helps guide future research as it identifies specific targets for therapy, aiding in the development of new drugs. One day we may have our cancer cure.
Finished: Leukemia Symptoms And Lessons: Is A Solution In Sight?
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