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Understanding CML
Leukemia is a type of cancer. CML is one of four main types of leukemia. CML starts with a change to a single stem cell. Both children and adults can get CML, but most CML patients are adults.
About 5,050 people in the United States are expected to be diagnosed with chronic myelogenous leukemia (CML) in 2009. It is estimated that approximately 22,475 people in the United States are living with CML (SEER, National Cancer Institute, 2009). Three new CML drugs (Gleevec®, Sprycel® and Tasinga®) have been approved since 2001. Other new treatments are being studied in clinical trials. Progress toward a cure is under way and the number of people with CML who are living well today is growing.
CML patients have what is called the "Philadelphia Chromosome" (Ph chromosome). Chromosomes are structures in the cells that contain genes. Every cell with a nucleus has chromosomes. Genes give instructions to the cells. The Ph chromosome is made when a piece of chromosome 22 breaks off and attaches to the end of chromosome 9. A piece of chromosome 9 also breaks off and attaches to the end of chromosome 22. The break on chromosome 9 involves a gene called Abl. The break on chromosome 22 involves a gene called Bcr. The Bcr and Abl genes combine to make the CML-causing gene called the Bcr-Abl cancer gene .
Phases of CML
There are three phases of CML:
The chronic phase The accelerated phase The blast crisis phase
Chronic Phase CML
Most patients are in the chronic phase of the disease when their CML is diagnosed. In this phase, CML symptoms are milder. White cells can still fight infection. Once patients in the chronic phase are treated, they can go back to their usual activities.
Accelerated Phase CML
In the accelerated phase, the patient may develop anemia, the number of white cells may go up or down, or the number of platelets may drop. The number of blast cells may increase and the spleen may swell. People with accelerated-phase CML may feel ill.
Blast Crisis Phase CML
Patients with blast crisis phase CML have an increased number of blast cells in the marrow and blood. The number of red cells and platelets drops. Patients may have infections or bleeding. They may also feel tired and have shortness of breath, stomach pain, or bone pain.
Causes and Risk Factors
Doctors do not know why the Bcr-Abl gene that leads to CML forms in some people but not in others. Some risk factors that may increase the risk of developing CML are:
Exposure to very high doses of radiation High-dose radiation therapy used to treat other cancers.
However, most people treated for cancer with radiation do not develop CML. And most people with CML were not exposed to high-dose radiation. There is no link between dental or medical x-rays and increased risk of CML.
You cannot catch CML from someone else.
Signs and Symptoms
People with CML may not have any symptoms at the time of diagnosis. They may be diagnosed following a medical examination for another condition or as part of a periodic checkup. CML signs and symptoms tend to develop gradually. Some signs and symptoms of CML are:
Tiring more easily Shortness of breath doing usual day-to-day activities Pale skin color Enlarged spleen leading to a "dragging" feeling on the upper left side of the abdomen Night sweats An inability to tolerate warm temperatures Weight loss.
Many of the signs and symptoms for CML are common to other illnesses. Most people with these signs and symptoms do not have CML.
Diagnosis
The diagnosis of CML is usually made with information from blood and bone marrow tests.
Blood Tests
The testing for CML includes blood cell counts and a blood cell examination.
Blood cell counts. The doctor orders a test called a complete blood count to check the numbers of blood cells. With CML, the red cell count is lower than normal. The number of white cells is higher than normal and may be very high. The number of platelets may be higher or lower than normal.
Blood cell examination. The cells are stained (dyed) and looked at (dyed) and looked at with an instrument called a light microscope. A person with CML has a small number of developing cells called "blast cells" in his or her blood. Blast cells are not found in the blood of healthy individuals.
Bone Marrow Tests and Cytogenetic Tests
Some signs of CML do not show in blood tests. The doctor has to look at a small number of cells (a sample) from the marrow. The samples of cells are obtained with tests known as a bone marrow aspiration and a bone marrow biopsy.
Samples of marrow cells are examined under a microscope. This is called a cytogenetic analysis. The examiner looks at a map of the chromosomes in the cell. The map is called a "karyotype." The Ph chromosome in a CML cell can be detected on the karyotype.
FISH or fluorescence in situ hybridization is a special test used to detect CML cells that may not show up on a standard cytogenetic test for the Ph chromosome.
PCR also known as Polymerase Chain Reaction is a very sensitive test that can detect CML cells that are not found by the FISH test. This test can detect a very small number of CML cells. A PCR test can be done on cells from blood or marrow.
Goals of CML Therapy
In the chronic phase of CML the goals of treatment are to
Return the levels of blood cells to normal Kill all cells that have the Bcr-Abl cancer gene.
In the accelerated phase or blast phase, the goal of CML treatment is to
Kill all cells that have the Bcr-Abl cancer gene or Return the disease to the chronic phase.
It is important to receive treatment in a center where doctors are experienced in the care of patients with CML.
Oral CML Therapy
Chronic Phase CML Treatment
In chronic phase CML, treatment usually returns the level of blood cells to normal. The spleen returns to its normal size. Most patients don't have infections or unusual bleeding.
Most CML patients begin treatment with a drug called Gleevec. This drug has been FDA-approved since 2001. Gleevec controls chronic phase CML for most people as long as they continue to take the drug. Patients who do not respond to the usual dose of Gleevec may respond to a higher dose.
Gleevec does not help all people with CML. Another drug may be used to treat a person with CML for one of these reasons:
Gleevec did not control the person's CML (called drug resistance" The person has strong side effects from Gleevec (called drug intolerance) Gleevec stopped working (called a loss of response).
For patients who cannot tolerate Gleevec or who have CML that is resistant to Gleevec, there are two newer FDA-approved drugs called Sprycel and Tasigna. Sprycel is approved to treat adults in all phases in all phases of CML with resistance or intolerance to prior therapy including Gleevec. Tasigna is approved to treat chronic and accelerated phases of CML in adults who are resistant or intolerant to prior therapy that included Gleevec. All three drugs, Gleevec, Sprycel and Tasigna are taken by mouth.
Most patients being treated for chronic phase CML can go about their day-to-day activities. With drug treatment most patients are symptom free for very long periods (called a remission). However, patients are not cured of CML with drug treatment. They are checked carefully for any signs that CML is returning (called a relapse). They will need regular health check-ups, including blood tests. From time to time patients will need a bone marrow test.
Accelerated Phase or Blast Crisis Phase Treatment
The goal in treating accelerated or blast crisis phase CML is to kill all cells that contain the Bcr-Abl gene or to return the patient's disease to the chronic phase.
Gleevec, and for certain patients, Sprycel or Tasigna, is an effective treatment for people who have accelerated or blast crisis phase CML. Other drugs—such as interferon, busulfan (Myleran®), cytarabine (Cytosar-U®) or hydroxyurea (Hydrea®)—may be used with those CML oral drugs.
Some people with CML have very high white cell counts at the time of diagnosis. This can reduce blood flow to the brain, lungs, eyes and other parts of the body. Hydrea may be used to decrease the white cell count. After the white cell count drops, oral drug therapy can be started.
Leukapheresis
Some patients have very high white cell counts at the time of CML diagnosis. This can reduce blood flow to the brain, lungs, eyes and other places in the body. Patients can have white cells removed by a special machine. This process is called leukapheresis. Leukapheresis can be used for women diagnosed with CML in the first months of pregnancy, when drug therapy may be harmful to the unborn baby.
Side Effects of Oral CML Therapy
Many treatment side effects go away or become less noticeable over time. Most can be handled without the need to stop the drug. Talk to your doctor about the possible side effects and long-term effects of your treatment.
Common side effects of Gleevec may include
Swelling from too much fluid in the body Puffiness around the eyes Nausea Vomiting Muscle cramps Diarrhea Rash
Gleevec may also cause loss of bone minerals. The doctor will check patients for these possible side effects.
Common side effects of Sprycel may include
Too few red cells, white cells and/or platelets Too much fluid in the chest Too much fluid in other tissues (edema) Diarrhea Headache Low calcium levels in the blood Slight changes in liver function.
Common side effects of Tasigna may include:
Too few white cells and/or platelets Rash Changes in liver enzymes Changes in pancreatic enzymes Nausea Constipation Diarrhea Itching
QT Prolongation
A possible side effect of Gleevec, Sprycel and Tasigna is a heart rhythm condition called QT prolongation. Your doctor will monitor you for this condition as needed. Some other medications can cause QT prolongation. Your doctor will give you a list of medications to avoid.
You can view, print or order the free LLS booklet Understanding Drug Therapy and Managing Side Effects for more information about the side effects of these and other drugs.
Stem Cell Transplantation
Stem cell transplantation is another important treatment for certain CML patients. Allogeneic stem cell transplantation is the only curative treatment for CML. It is a treatment to restore a person's marrow. The transplanted stem cells go from the person's blood to his or her marrow. The cells start a new supply of red cells, white cells and platelets. The person needs to have a "matched" stem cell donor for the transplant. The donor can be a sibling or another person with stem cells that "match" the stem cells of the transplant patient.
About 7 out of 10 people who have an allogeneic transplant are cured of their CML. But this procedure has a high risk of serious complications. This treatment is most successful in younger patients. It may be considered for people up to about 60 years of age who have a matched donor and who do not have a good response to oral drug treatment. The decision to do a transplant for CML patients depends on:
The patient's age The patient's overall health How well the donor cells and the patient cells match The degree of the patient's response to oral drug therapy
If a stem cell transplant is suggested for you, your doctor will discuss the benefits versus the risks of having this treatment. Doctors are studying a type of stem cell transplant called a reduced-intensity transplant (nonmyeloablative stem cell transplant). It may be helpful for older patients who are not eligible for allogeneic stem cell transplantation.
Donor Lymphocyte Infusion
CML patients whose disease returns after an allogeneic stem cell transplant (called a relapse) may be treated with Gleevec, Sprycel, Tasigna or other CML drugs. Another treatment choice is a second transplant. Or patients may be treated with a donor lymphocyte infusion (an infusion of white cells called lymphocytes from the original stem cell donor).
Clinical Trials
Clinical trials are used to study new drugs and new combinations of drugs, new treatments or new uses for approved drugs or treatments. There are CML clinical trials for people of all ages.
Some clinical trials test new ways to use drugs that are already approved. For example, changing the amount of the drug or giving the drug along with another type of treatment might be more effective. Some clinical trials combine drugs for CML in new sequences or doses.
Ongoing studies are comparing Gleevec to Sprycel (or Tasigna) for newly diagnosed individuals. Study data will help in identifying which patients are least likely to respond, or most likely to lose a response, to Gleevec therapy.
New drugs are being studied for people with CML that does not respond to Gleevec, Sprycel or Tasigna.
Vaccine Therapy
Various forms of vaccine therapy are being studied. It is possible that one day vaccines will be able to treat (not prevent) the disease by using a person's own immune cells to attack his or her CML cells.
Reduced-Intensity Transplant
Doctors are working to make allogeneic stem cell transplants safer. A type of transplant called a reduced-intensity transplant is under study in clinical trials. A reduced-intensity transplant uses a lower dose of conditioning chemotherapy than the dose used with a standard allogeneic stem cell transplant. This treatment is also called a nonmyeloablative transplant. Older and sicker patients may be helped by this treatment.
Ask your doctor if treatment in a clinical trial is right for you. You can also call the Information Resource Center for information about clinical trials or use the LLS-supported, free clinical trials service TrialCheck®.
See the free LLS publications The CML Guide. Information for Patients and Caregivers and Chronic Myelogenous Leukemia for more details about clinical trials.
Tracking Treatment Response
Measuring treatment response is very important. Blood and marrow tests are used to track a person's level of response to treatment. The results are used to help the doctor decide if the person's CML is well controlled or if there is a need to
Increase the dose to try for a better response Decrease or stop the drug briefly because of side effects Change to a different drug or combination of drugs to better control the CML Change to a different drug or combination of drugs to manage side effects.
General Guidelines There are general treatment response guidelines for the first year of CML drug therapy. But keep in mind that people with CML respond to treatment in different ways. Blood tests and/or bone marrow tests may be used to determine the level of CML drug therapy response. A person's response is measured against his or her lab test results at the start of treatment. The number of red cells, white cells, platelets and CML cells is measured on a regular basis throughout treatment.
After diagnosis, marrow testing is usually repeated at 6 and 12 months within the first year of diagnosis.
Many doctors do bone marrow testing one to two times a year in the second year after diagnosis.
Doctors may repeat the bone marrow tests every 12 to 18 months once a good response is achieved.
Your doctor may use the terms hematologic, cytogenetic or molecular response (remission).
Hematologic Response - A complete hematologic response means that the numbers of white cells, red cells and platelets are normal or near normal. A complete blood count is done to measure the numbers of white cells, red cells and platelets, and the levels of hemoglobin (a protein in red cells that carries oxygen) and hematocrit (the amount of blood that has red cells). Cytogenetic Response - A complete cytogenetic response means that there are no cells that can be detected with the Ph chromosome and the Bcr-Abl cancer gene. The FISH test is done to measure the number of cells with the Ph chromosome and the Bcr-Abl cancer gene. Molecular Response - A partial molecular response means that there is a reduction in the number of cells with the Bcr-Abl cancer gene. A major molecular response means that there is a 1,000-fold decrease in the level of cells with the Bcr-Abl gene from the level measured at the start of treatment. A complete molecular response means that the Bcr-Abl cancer gene cannot be detected by PCR. Remaining CML cells that cannot be detected by PCR are called "minimal residual disease." PCR is done to measure the number of cells with the Bcr-Abl cancer gene. The same laboratory should be used each time for PCR testing if possible. This is because results may vary from lab to lab.
CML-Related Disorders
The name chronic myelogenous leukemia is sometimes used for other types of myelogenous leukemia that have a chronic course. Chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML) and chronic neutrophilic leukemia (CNL) have some of the signs and symptoms of CML.
These diseases are less common myeloproliferative diseases that are subtypes of myelogenous leukemia and progress more slowly than acute myelogenous leukemia. People with these diseases do not have the Bcr-Abl gene; this is one of several distinguishing features used to make a diagnosis. These patients are not expected to (and have been proven not to) respond to treatment with Gleevec.
For more information on these types of CML, see the free LLS fact sheet, Chronic Myelomonocytic Leukemia (CMML) and Juvenile Myelomonocytic Leukemia.
Understanding AML
About 13,290 Americans are expected to be diagnosed with acute myelogenous leukemia (AML) in 2008. The chance of getting AML increases with age. However, children and adults of any age can develop AML. About one in five children with leukemia has AML. The goal of treatment for AML is to bring about a remission or to cure the disease.
The number of patients with AML who enter remission, stay in remission for years or are cured has increased significantly over the past 30 years.
Causes and Risk Factors
AML starts with a change to a single cell in the bone marrow. With AML, the leukemic cells are often referred to as blast cells.
Medical researchers are working to understand the cell changes that lead to AML.
Down syndrome and other uncommon genetic disorders such as Fanconi anemia and Shwachman-Diamond syndrome and others are associated with an increased risk of AML.
Some other risk factors associated with AML are:
Some types of chemotherapy Radiation therapy used to treat other cancers Tobacco smoke Exposure to large amounts of benzene
Most people who have these risk factors do not get AML - and most people with AML do not have these risk factors.
You cannot catch AML from someone else. Very rarely, more cases of AML than would be expected are diagnosed within the same family. It is thought that children in these families inherit a gene that makes them more susceptible to developing AML. Research to improve the understanding of familial cancers and effective medical management of them is underway.
Signs and Symptoms
Some of the signs and symptoms for AML are common to many illnesses. Some changes that a person with AML may have are:
Tiredness or no energy Shortness of breath during physical activity Pale skin Swollen gums Slow healing of cuts Pinhead-size red spots under the skin Prolonged bleeding from minor cuts Mild fever Black-and-blue marks (bruises) with no clear cause Aches in bones or knees, hips or shoulder.
The best advice for any person troubled by any of these symptoms is to see a healthcare provider.
Diagnosis
Blood and Bone Marrow TestsBlood and bone marrow tests are done to diagnose AML. A bone marrow aspiration and a bone marrow biopsy are two of the tests that are done. A bone marrow aspiration shows the cell-type and certain
abnormalities by looking at proteins on the cell's surface. It can be used for cytogenetic analysis and other tests. Cytogenetic analysis is a lab test to examine the chromosomes of the leukemic blast cells. Some changes to chromosomes give doctors information about how to treat their AML patients.A bone marrow biopsy shows chromosome and gene abnormalities and how much disease is in the marrow. Both tests are also done to see if treatment is destroying leukemic blast cells. The doctor uses information from these tests to decide if leukemia is present, the type of treatment the patient needs and the best treatment for the patient. The doctor will also consider the patient's age, the general health of the patient, and the presence of certain changes to chromosomes to determine the best treatment for the patient.
Subtypes of AML
There are different types of AML. These are called subtypes. Most patients diagnosed with AML have one of eight different subtypes:
Designation Cell Subtype
M0 Myeloblastic, on special analysis
M1 Myeloblastic, without maturation
M2 Myeloblastic, with maturationM3 PromyelocticM4 MyelomonocyticM5 MonocyticM6 ErythroleukemiaM7 Megakaryocytic Doctors look at the AML cells in a patient's marrow or blood to identify the patient's subtype of AML. Treatment for AML may vary by subtype. For example, acute promyelocytic leukemia (APL) and acute monocytic leukemia are subtypes of AML that need different treatment than other subtypes of AML.
Treatment
Patients with AML need to start chemotherapy right away. It is important to get medical care in a center where doctors are experienced in treating AML patients.
There are two parts of AML treatment, called induction therapy and consolidation therapy. The aim of induction therapy is to kill as many AML cells as possible and get blood cell counts back to normal over
time. When the aim of induction therapy is achieved it is called a remission. A patient in remission feels better over time and leukemia cells can't be seen in his or her blood or marrow.
Induction therapy is done in the hospital. Patients are often in the hospital for three to four weeks. Some patients may need to be in the hospital longer.
Many different drugs are used to kill leukemic cells. Each drug type works in a different way to kill the cells. Combining drug types can strengthen the effects of the drugs. New drug combinations are being studied. Two or more chemotherapies are usually used together to treat AML. Some drugs are given by mouth. Most chemotherapies are given through a catheter placed into a vein, usually in the patient's upper chest.
The first round of chemotherapy usually does not get rid of all the AML cells. Most patients will need more treatment. Usually the same drugs are used for more rounds of treatment to complete induction therapy.
More treatment is usually needed even after a patient with AML is in remission. This second part of treatment is called consolidation therapy. It is needed because some AML cells remain that are not found by common blood or marrow tests. Consolidation therapy is also done in the hospital. As with induction therarpy, patients may be in the hospital for three to four weeks, or sometimes longer. Consolidation therapy may include chemotherapy with or without an allogeneic stem cell transplant or autologous stem cell transplant.
Follow-Up Visits Patients who are in remission still need to see the doctor regularly for exams and blood tests. Bone marrow tests may be needed too. The doctor may recommend longer waits between follow-up visits if a patient continues to be disease-free.
Refractory Leukemia and Relapsed Leukemia Some patients still have AML cells in their marrow after treatment. This is called refractory AML. With refractory AML, drugs that were not used to treat the patient's AML in the first part of treatment may be given. Allogeneic stem cell transplantation also may be used for certain patients.
For patients who relapse, the same or different drugs may be given, or stem cell transplantation may be used. A drug called gemtuzumab ozogamicin (Mylotarg®) is being used to treat some older patients who have relapsed AML.
Treatment in Children
There are about 4,220 new cases of childhood leukemia expected to be diagnosed in 2008 in the United States (for children 0-19 years of age). Induction therapy for children with AML starts with two or three drugs. Stronger treatment is needed after a child with AML is in remission. This is called intensive consolidation therapy. It is given because usually some AML cells remain after induction therapy. These AML cells do not show up in standard blood or marrow tests. Consolidation therapy in children includes a number of chemotherapies.
About four out of five children with AML go into remission. About half of children with AML have no signs of disease after five years. Most of these children are considered cured.
AML treatment is less likely to bring about a remission or cure when children:
Have acute myelogenous leukemia with very high white cell counts. Are younger than 1 year of age. Have certain chromosomes in their AML cells that are not normal.
Allogeneic stem cell transplants may be used in children who are not doing well or who relapse after high-dose chemotherapy. Doctors will discuss the benefits and risks with parents and older children.
Long-Term and Late Effects of Treatment for Children Transplant and other treatment can cause long-term or late effects involving a child's growth, hormones, heart and other parts of the body. Treatment for leukemia can also cause problems with learning skills. But special education methods can help these children learn. It is important to identify problems early. Talk to the doctor about when your child's learning skills should be assessed.
Treatment in Older Adults
At least half of patients are over 65 years old when their disease is diagnosed. Some healthy older patients can be treated with the same doses of chemotherapy as younger adults. Sometimes older patients have other medical problems, such as heart disease, kidney or lung disease, or diabetes. The doctor takes these other medical conditions into account to decide which drugs and dosages to use. The doctor will also consider the patient's type of AML, his or her physical ability to handle the treatment and feelings about the treatment approach.
Treating Special AML Subtypes
Acute Promyelocytic Leukemia Treatment Acute promyelocytic leukemia is the most curable form of AML. People with acute promyelocytic leukemia are treated with a substance that comes from vitamin A called all-trans retinoic acid (ATRA). This treatment is given along with chemotherapy. It is often successful in bringing this type of leukemia into remission. Another treatment for acute promyelocytic leukemia is arsenic trioxide (ATO). It may be given to patients whose leukemia has returned or cannot be brought under control with chemotherapy and ATRA.
Acute Monocytic Leukemia Treatment In one type of AML, called acute monocytic leukemia, the leukemia cells are more likely to invade the lining of the spinal canal or brain. The patient gets chemotherapy directly into the spinal canal to treat these hard-to-reach cells. A needle is placed into the spinal canal during a procedure called a spinal tap. Spinal fluid is removed and chemotherapy is injected into the spinal canal. Sometimes radiation therapy may be used to treat a large mass of leukemia cells in the spine or brain.
Allogeneic Stem Cell Transplantation
Chemotherapy used to treat AML also kills the healthy stem cells in the marrow. Allogeneic stem cell transplant is used to treat some AML patients.
There are two reasons for doing an allogeneic stem cell transplant:
1. To give strong doses of chemotherapy to kill more AML cells.2. To give the patient the donor immune cells to attack any AML cells that remain.
When the donor cells attack the AML cells it is called graft versus leukemia or GVL. GVL is also called graft versus cancer.
Allogeneic stem cell transplant can be a high-risk procedure. For this reason, it may not be a good treatment for some AML patients. The decision to do a transplant depends on the patient's age and overall health, the chances that chemotherapy alone will cure his or her AML, and the patient's understanding of the benefits and risks of the transplant. Doctors will discuss these with patients and parents of young children with AML.
AML patients who have an allogeneic stem cell transplant are usually between the ages of 1 and 50 and are in remission. In addition, the patient needs to have a matched donor.
Doctors are studying a type of stem cell transplant called a nonmyeloablative stem cell transplant. This treatment may be helpful for older patients.
Autologous Stem Cell Transplantation
Patients who do not have a matched donor for a stem cell transplant may be given very high doses of chemotherapy and an autologous stem cell transplant instead. The goal of an autologous stem cell transplant is to restore the body's ability to make normal blood cells after high-dose chemotherapy.
Disease and Treatment Side Effects
Not all patients have side effects.
However, chemotherapy and radiation therapy often affect a person's blood counts. The number of red cells may decrease (called anemia). Transfusions of red cells (blood cells that are donated and given to the patient) are usually needed to increase the red cell count. Patients usually have a drop in the number of platelets. If a patient's platelet count is very low he or she usually needs a platelet transfusion to prevent or treat bleeding. A long-lasting and big drop in white cells may lead to an infection. Such infections are usually treated with antibiotics, until the normal white cell count goes up and the infection clears up. Patients with an infection may also have coughing, sore throat, pain when urinating, or frequent loose bowel movements. Or, fever or chills may be the only signs of infection.
To lower the risk of bacterial, viral and fungal infections, patients, visitors and medical staff need to wash their hands well. Also, the patient's central line must be kept clean and patients should follow all medical advice for taking care of their teeth and gums.
Complete blood counts are usually done throughout treatment. If the red cell counts or platelet counts are too low transfusions may be necessary. Growth factors are sometimes given to increase the number of white cells if they are too low. G-CSF (Neupogen® or Neulasta®) and GM-CSF (Leukine®) are drugs that increase white cell counts. Your doctor may talk about neutropenia (a lower than normal neutrophil count) and absolute neutrophil count or ANC, which is the number of white cells that are neutrophils.
Other side effects of treatment include: mouth sores, rashes, dry mouth, diarrhea, nausea, constipation, hair loss, vomiting, or changes in the way certain foods taste. Drugs or other therapies may be helpful to prevent or treat nausea, vomiting and other side effects.
Chemotherapy may cause the amount of uric acid to increase in the blood of some AML patients. (Some patients also have a buildup of uric acid from the disease itself.) Uric acid is a chemical made in the body. A high level of uric acid can cause kidney stones. Patients with high uric acid levels may be given a drug called allopurinol (Aloprim®, Zyloprim®) by mouth. Another drug used to treat high uric acid levels is called rasburicase(Elitek®), which is given by vein.
Clinical Trials
Clinical trials are used to study new drugs, new treatments or new uses for approved drugs or treatments. Research has contributed to the growing number of patients with AML who enter remission, stay in remission for years or are cured. One of the challenges for future research is to develop treatments that help more patients.
Scientists are trying to create new drugs or find them from natural sources. They are also studying new combinations of drugs already being used. Scientists are studying ways to boost the body's natural defenses, called immunotherapy. The goal is to kill or prevent the growth of AML cells.
Scientists are studying a type of stem cell transplant, called a nonmyeloablative stem cell transplant.
Scientists are studying cytokines, natural substances made by cells. Cytokines can also be made in the lab. They can be used to help restore normal blood cell counts during treatment or boost the immune system to better attack the leukemia cells.
Leukemia-specific therapy, based on a patient's specific subtype of leukemia, such as the type of chromosome changes, is being studied.
The AML cells of some patients are not as easily killed by drugs as those of other patients. This is called drug resistance. Scientists are trying to understand why some AML cells are resistant to the effects of chemotherapy. This will help them develop better treatments.
Scientists are studying the exact genetic changes that cause a normal cell to become an AML cell. This research is leading to the development of new treatments. These treatments could block the effects of cancer-causing genes (called oncogenes).
Gemtuzumab ozogamicin (Mylotarg®) is FDA-approved to treat CD33 positive AML patients in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy. This drug is being studied in combination with other drugs to treat relapsed AML and is
also being studied in combination with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) to treat acute promyelocytic leukemia.
Some other drugs under study for future use in AML treatment include:
• Farnesyl transferase inhibitors, for example tipifarnib (Zarnestra®) or lonafarnib • FLT-3 inhibitors • Proteasome inhibitors, such as bortezomib (Velcade®) • Multi-drug Resistance Modulators, such as cyclosporine A or PSC-833 • Antisense molecules (Genasense®, GTI-2040) • Hypomethylating agents, such as decitabine (Dacogen®) • Histone deacetylase inhibitors, such as depsipeptide.
Understanding ALL
Acute lymphocytic leukemia (ALL) is a type of blood cancer. Other names for ALL are acute lymphoblastic leukemia and acute lymphoid leukemia.
About 5,430 people in the United States are expected to be diagnosed with ALL in 2008. It is the most common type of leukemia in children under age 15. The risk of getting ALL increases in people ages 45 and older. However, people can get ALL at any age.
Most children with ALL are cured of their disease after treatment.
Causes and Risk Factors
ALL starts with a change to a single cell in the bone marrow. Scientists are studying the exact genetic changes that cause a normal cell to become an ALL cell.
Few factors have been associated with an increased risk of developing ALL. Exposure to high doses of radiation therapy used to treat other types of cancer is one known risk factor. Other possible risk factors are continually under study. ALL is not contagious (catching).
ALL occurs at different rates in different geographic locations. There are higher rates in more developed countries and in higher socioeconomic groups. Scientists continue to explore possible relationships with life-style or environmental factors but no firm conclusions have yet been reached. This suggests that many factors may be involved. At the present time there is no known way to prevent most cases of the disease.
Information About Phosphocol P32. Phosphocol P32 is a prescription drug approved to treat adults with fluid in the abdominal or chest cavity caused by cancer or infection. Safety and effectiveness in children has not been established. The United States Food & Drug Administration (FDA) updated the safety information of this drug in August 2008 following reports linking Phosphocol P32 to leukemia, when used in an unapproved way to treat children with bleeding between the joints caused by hemophilia. The labeling of Phosphocol P 32 was modified by the manufacturer, Covidien Ltd. in August
2008 to reflect this risk. Information about the leukemia cases [two children (ages 9 and 14) with hemophilia developed acute lymphocytic leukemia approximately 10 months after intra-articular injections of Phosphocol P 32 (0.6 and 1.5 mCi total dose] was added to the "Warnings" section of the Phosphocol P 32 label. Also, "leukemia in children" is now noted as a risk in the label's "Adverse Events" section. Safety information is posted on the FDA Medwatch Web site (August 2008). The manufacturer strongly encourages medical professionals and their patients to follow the guidelines outlined in the prescribing information included with Phosphocol P 32. To read Covidien's communication to physicians click here August 29, 2008 manufacturer's letter to physicians.
Signs and Symptoms
Some signs or symptoms of ALL are similar to other more common and less severe illnesses. Specific blood tests and bone marrow tests are needed to make a diagnosis. A person with ALL may have:
Aches in arms, legs, back Black-and-blue marks for no apparent reason Enlarged lymph nodes Fever without obvious cause Headaches Pale-looking skin Pinhead-size red spots under the skin Prolonged bleeding from minor cuts Shortness of breath during physical activity Tiredness Vomiting.
The best advice for any person troubled by symptoms such as a lasting, low-grade fever, unexplained weight loss, tiredness or shortness of breath is to see a healthcare provider.
Diagnosis
Blood and bone marrow tests are done to look for leukemia cells. A CBC (complete blood count) is used to help diagnose ALL. A bone marrow aspirate and a bone marrow biopsy are two of the tests that are done. An aspirate is done to take a close look at the cells in the marrow in order to look for abnormal cells such as leukemic blast cells. It can also be used for cytogenetic analysis, immunophenotyping and other tests. The biopsy gives information about how much disease is in the marrow. Immunophenotyping is used to find out if the patient's leukemia cells are B cells or T cells. Most people with ALL have the B-cell type. Most cases of the B-cell type are called precursor B-cell type.
The doctor uses information from these tests to decide the type of drug therapy a patient needs and how long treatment will last. Bone marrow tests are also done to see if treatment is destroying leukemic blast cells.
To decide the best treatment for the patient, the doctor may also consider:
The patient's age The number of ALL cells in the blood
If the ALL has spread to the covering of the brain or spinal cord If there are certain chromosomal changes.
Treatment
Patients with ALL need to start chemotherapy right away. It is important to get medical care in a center where doctors are experienced in treating patients with ALL.
The goal of treatment for ALL is to cure the disease. Children with ALL are likely to be cured of their disease. The number of adult patients who have remissions has increased. The length of remissions in adults has improved.
There are two parts of treatment for ALL, called induction therapy and post-induction therapy. The aim of induction therapy is to:
Kill as many ALL cells as possible Get blood counts back to normal And to get rid of all signs of the disease for an extended period of time.
This is called a remission.
Some drugs used to treat ALL are given by mouth. Other drugs are given by placing a catheter in a vein - usually in the patient's upper chest. During induction therapy most patients are treated with more than one drug and they may be given several drugs in combination. Each drug type works in a different way to kill the cells. Combining drug types can strengthen the effects of the drugs. Some of the drugs used to treat ALL are clofarabine, cytarabine, daunorubicin, methotrexate, mitoxantrone, cyclophosphamide, vincristine, pegaspargase, imatinib mesylate, prednisone and dexamethasone.
Patients with ALL often have leukemic cells in the lining of the spinal cord and brain. The procedure used to check the spinal fluid for leukemic cells is called a spinal tap. The cells cannot always be found in an exam of the spinal fluid.
To prevent leukemia in the central nervous system (CNS) leukemia, all patients who are in remission have the lining of the spinal cord and brain treated. In some cases, treatment is needed for ALL that has already affected the lining of the spinal cord and brain (CNS leukemia) and is causing problems such as headache, nausea and vomiting, and blurred vision. Parts of the body that aren't easily reached with chemotherapy given by mouth or IV - such as the lining of the spinal cord and brain - are treated by injection into the spinal fluid. Drugs such as methotrexate or cytarabine are injected into the spinal fluid either to prevent or treat CNS leukemia.
When the treatment is for CNS leukemia, a spinal tap is done. Then spinal fluid is removed and chemotherapy is injected into the spinal canal.
Radiation therapy may be given to the spine or brain. Spinal taps are done from time to time to check if leukemic cells are being killed and to give more doses of chemotherapy. Sometimes both chemotherapy and radiation therapy are used.
Many ALL patients build up uric acid in their blood from their disease. Uric acid is a chemical made in the body. The use of chemotherapy also increases the uric acid. A high level of uric acid can cause kidney stones. Patients with high uric acid levels may be given a drug called allopurinol (Aloprim®, Zyloprim®) by mouth or IV. Another drug used to treat high uric acid levels is called rasburicase (Elitek®).
Post-Induction Therapy More treatment is needed even after a patient with ALL is in remission. This is called post-induction therapy. It is given in cycles for two to three years. Post-induction therapy is given because some ALL cells remain that are not found by common blood or marrow tests. For most people, the postremission therapy drugs used are not the same drugs used during induction therapy. The doctor considers many things to decide the kind of post-induction therapy a patient needs, such as:
The patient's response to induction therapy. Whether the patient has certain chromosomal abnormalities.
High-risk types of ALL - such as T-cell ALL, infant ALL and adult ALL - are usually treated with higher doses of drugs during induction and post-induction therapy. One treatment plan is to use higher doses of drugs and give them for a longer time. Allogeneic stem cell transplant may be a good treatment for some high-risk ALL patients.
Ph-Positive ALL-Induction/Post-Induction
About one out of five adults with ALL and a small number of children with ALL have a type called Ph-positive (or Philadelphia-positive) ALL.
Ph-positive ALL may be treated with imatinib mesylate, also called Gleevec® or with other related drugs, such as dasatinib (Sprycel®) or nilotinib (Tasigna®). These drugs are given with chemotherapy. Gleevec® (or Sprycel® or Tasigna®) is given by mouth. Doctors are studying how well this treatment works in patients with Ph-positive ALL.
During post-induction therapy, Gleevec® (or another related drug) is given with other drugs. Usually people with Ph-positive ALL stay on Gleevec® (or another related drug) after post-induction therapy is completed.
Allogeneic Stem Cell Transplant Allogeneic stem cell transplant is a treatment used for some patients with ALL. The main purpose of doing the transplant is to give strong doses of chemotherapy or radiation therapy to kill the ALL cells. This will also kill the healthy stem cells in the marrow. The transplanted donor stem cells help start a new supply of red cells, white cells and platelets.
Allogeneic stem cell transplant is a high-risk procedure. For this reason, it may not be a good treatment for some ALL patients. Allogeneic stem cell transplant may be a choice for adult ALL patients if:
They are not doing well with other treatments. The expected benefits of stem cell transplant exceed the risks. There is a donor.
Stem cell transplant is usually not considered for a child unless:
Doctors have determined that the child's type of ALL is not likely to respond well to chemotherapy.
Chemotherapy has not worked well. The child has relapsed ALL.
Side Effects of Treatment
Not all patients have treatment side effects. Patients who experience side effects should speak to their treatment teams about how to manage their side effects.
Possible side effects of treatment for ALL include:
The number of red cells may decrease (called anemia). Transfusions of red cells (blood cells that are donated and given to the patient) may be needed to increase red cells.
Patients also may have a drop in the number of platelets. If a patient's platelet count is very low he or she may need a platelet transfusion to prevent bleeding.
A big drop in white cells may lead to an infection. Such infections are usually treated with antibiotics, until the white cell count goes up and the infection clears up. For adults, growth factors are sometimes given to increase white cells. G-CSF (Neulasta® or Neupogen®) and GM-CSF (Leukine®) are drugs that increase the number of white cells. The doctor may talk about the absolute neutrophil count or ANC, which is the number of neutrophils, a type of white cell a person has to fight an infection. Fever or chills may be the only signs of infection. Patients with an infection may also have:
o Coughing o Sore throat o Pain when urinating o Frequent loose bowel movements.
To lower the risk of infection:
The patient, the patient's visitors and medical staff need to wash their hands well. The patient's central line must be kept clean. Patients on chemotherapy should take good care
of their teeth and gums.
Chemotherapy affects the parts of the body where new cells form quickly. This includes the inside of mouth and bowel, and the skin and hair. Some other chemotherapy side effects are:
Mouth sores Diarrhea Hair loss Rashes Nausea Vomiting.
Drugs and other therapies can be given to prevent or treat nausea or vomiting.
Follow-up Visits Patients who have finished all of their therapy still need to go to their doctors regularly for exams and tests. The doctor may recommend longer periods of time between follow-up visits if a patient continues to be disease free.
Treatment for ALL can cause long-term or late effects. Children should be checked for treatment effects on growth or learning that may not take place right away. It is important to identify problems early. Talk to the doctor about when your child's learning skills should be assessed. Some children will need special help with schoolwork during and after treatment.
Relapsed or Refractory ALL
Some patients have a remission after treatment but then ALL cells return later - this is called a relapse. Other patients with ALL may still have ALL cells in the marrow even after treatment (refractory leukemia).
For patients who relapse, the same or different drugs may be given, or be used. A drug called clofarabine (Clolar®) is being used to treat some children (ages 1 to 21) with relapsed and refractory ALL.
In refractory leukemia, drugs that were not used to treat the patient's ALL in the first round of treatment may be given. Allogeneic stem cell transplantation also may be used.
Clinical Trials
Clinical trials are used to study new drugs, new treatments or new uses for approved drugs or treatments. These are some of the types of trials under way:
Leukemia-specific therapy, based on a patient's specific type of leukemia - such as the type of chromosome changes - is being studied.
The ALL cells of some patients are not as easily killed by drugs as those of other patients. This is called drug resistance. Scientists are trying to understand why some ALL cells are resistant to the effects of chemotherapy. This will help them develop better treatments.
Scientists are studying ways to boost the body's natural defenses, called immunotherapy. The goal is to kill or prevent the growth of ALL cells.
Blood cell growth factors can be used to help restore normal blood cells during treatment.
Scientists are studying the exact genetic changes that cause a normal cell to become an ALL cell. This research is leading to the development of new treatments. These treatments could block the effects of cancer-causing genes called oncogenes.
Gene profiling will be used more in the future to design more specific treatments for the different types of leukemia. New targeted treatments are being developed for ALL.
Many therapies, such as nilotinib, are being studied in clinical trials for Ph-positive ALL and other high-risk types of ALL. T-cell ALL, infant ALL and adult ALL are other high-risk types of ALL.
Doctors are studying a type of stem cell transplant, called a nonmyeloablative stem cell transplant (also called a reduced-intensity transplant).
Understanding CLL
Chronic lymphocytic leukemia (CLL) is one of four main types of leukemia. About 15,490 new cases of CLL will be diagnosed in 2009. It is estimated that 85,710 people in the United States are living with or are in remission from CLL.
Many people with CLL live good-quality lives for years with medical care. There are a number of treatments for CLL. In recent years new therapies have been approved and other possible new treatments are being studied in clinical trials. Progress toward a cure is under way.
CLL starts with a change (mutation) to the DNA of a single cell called a lymphocyte. In 95 percent of people with CLL, the change occurs in a B lymphocyte. In the other 5 percent, the cell that transforms from normal to leukemic has the features of a T lymphocyte or an NK cell. B-cells, T-cells and NK-cells are types of lymphocytes. The diagram below illustrates the process of lymphocyte development.
Click here to view a larger version of this diagram.
Over time, the CLL cells multiply and replace normal lymphocytes in the marrow and lymph nodes. The high number of CLL cells in the marrow may crowd out normal blood-forming cells, and CLL cells are not able to fight infection like normal lymphocytes do.
Incidence
CLL is more common in people who are 60 years and older than in younger adults. The number of people with CLL starts to increase after age 50.
A small number of people are diagnosed with CLL in their 30s and 40s. Children do not get CLL.
Causes and Risk Factors
Doctors do not know what causes the cell-change that leads to CLL. There is no way to prevent CLL. You can't catch CLL from someone else.
CLL has generally not been associated with any environmental or external factors. However, the Institute of Medicine of the National Academy of Sciences issued a report, which concluded that there was "sufficient evidence of an association" between herbicides used in Vietnam and CLL. For more information, visit the US Department of Veterans Affairs Web site or call (800) 827-1000.
In certain families, more than one blood relative has CLL. However, this is not common. Doctors are studying why some families have a higher rate of CLL.
Symptoms and Signs
CLL signs and symptoms usually develop slowly. Some people with CLL do not have any symptoms. These people may find out they have CLL after a regular medical checkup shows certain changes in the blood. Early in the course of the disease, CLL often has little effect on a person's well-being.
Many of the signs and symptoms of CLL are more likely to be caused by other illnesses. Specific blood tests and bone marrow tests are needed to make a diagnosis.
Some signs and symptoms of CLL include
Tiring more easily. People may have less energy due to fewer healthy red cells and more CLL cells.
Shortness of breath during normal activities. This is due to fewer healthy red cells and more CLL cells.
Swollen lymph nodes or spleen. High numbers of CLL cells can gather in the lymph nodes or spleen as the number of CLL cells grows.
Infections. People with a very high number of CLL cells building up in the marrow may have repeated infections of the skin or other parts of the body. This is because CLL cells cannot fight infection as well as healthy lymphocytes.
Weight Loss. Some people with CLL lose weight because they eat less and/or because they are using more energy.
Some patients may also have other symptoms, such as aches, fever or night sweats.
Diagnosis
The diagnosis of CLL is usually made from blood and bone marrow tests.
Blood Tests
The testing for CLL includes blood cell counts and a blood cell examination.
Blood cell counts. A person with CLL will have a high lymphocyte count. He or she may also have a low red cell count and a low platelet count.
Blood cell examination. The CLL cells are usually examined with an instrument called a "flow cytometer." The test is called flow cytometry or immunophenotyping. The test is done to find out if CLL is the reason for the high lymphocyte count. Flow cytometry also shows if the CLL is B-cell CLL or T-Cell CLL. B-cell CLL is most common.
Immunoglobulin Test. Doctors check the immunoglobulin level in the blood. Immunoglobulins are proteins that help the body fight infection. People with CLL may have low levels of immunoglobulins. A low immunoglobulin level may be the cause of repeated infections.
Bone Marrow Tests and Cytogenetic Tests
Bone marrow tests are not usually needed to make a CLL diagnosis. But it's often helpful to have a bone marrow aspiration and a bone marrow biopsy before treatment begins. The results of these tests serve as a baseline that is used later on to assess the effects of treatment.
FISH or fluorescence in situ hybridization is a test used to see if there are changes to the chromosomes of the CLL cells. About half of the people with CLL have CLL cells with chromosome changes. FISH may give doctors information about which patients need more medical follow-up. FISH can be done with a sample of cells from blood or marrow.
Goals of CLL TherapyIt is important to get treatment in a center where doctors are experienced in the care of patients with CLL.
The goals of CLL treatment are to
Slow the growth of CLL cells Provide long periods of remission (when there are no signs of CLL and/or people feel well
enough to carry on their day-to-day activities) Help people to feel better if they have infections, fatigue or other symptoms.
Treatment Planning and Staging
The treatment plan for a person with CLL depends on the
Stage of the CLL (low, intermediate or high risk) Physical exam and lab test results Person's overall health Person's age (for some treatments).
CLL Staging
Many doctors use a system called staging to help plan treatment for people with CLL. Many doctors use the "Rai staging system," which defines a person's risk as follows:
Low-Risk CLL
High lymphocyte count in the blood and the marrow.
Intermediate-Risk CLL
High lymphocyte count in the blood and the marrow Enlarged (swollen) lymph nodes
or High lymphocyte count in the blood and the marrow Enlarged (swollen) lymph nodes, liver or spleen.
High-Risk CLL
High lymphocyte count in the blood and the marrow Anemia (low red cell count)
or High lymphocyte count in the blood and the marrow A low platelet count.
Other lab test results may show signs of faster-growing disease (higher-risk CLL). This means the person needs closer follow-up with the doctor.
Blood Lymphocyte Doubling Time - a lymphocyte number that doubles in one year means that the person needs closer follow-up.
Beta 2-Microglobulin (B2M) - B2M is a protein on CLL cells. A higher level of B2M may mean there are more CLL cells.
CLL Treatment
Watch and Wait
The watch and wait approach means that a doctor observes a person's condition with physical exams and lab tests. The doctor does not treat the person with drugs or other therapies during the watch and wait period.
Some patients with CLL may think that they should have treatment right away. But for people with low-risk (slow-growing) disease and no symptoms, it is best not to start treatment. The watch and wait approach allows the patient to avoid side effects until treatment is needed. Patients in watch and wait need follow-up visits with the doctor. At each office visit, the doctor will check for any health changes. The results of exams and lab tests over time will help the doctor advise the patient about when to start treatment and the type of treatment to have.
A doctor may advise the patient to begin treatment if one or more of these signs develop:
The number of CLL cells is much higher than it was The number of normal cells is much lower than it was The lymph nodes have become larger The spleen has become larger
A patient with any or all of these signs may start to feel too tired for normal daily activities.
Drug Treatment
People who have intermediate- and higher-risk (faster-growing) CLL are usually treated with combination chemotherapy and/or monoclonal antibody therapy.
Chemotherapy is treatment with drugs that kill or damage cancer cells. Some drugs are given by mouth. Other drugs are given through a vein by placing a small needle in the arm (called an IV). Two or more drugs are often used together. The FDA-approved drugs fludarabine (Fludara®), cyclophosphamide (Cytoxan®), bendamustine (Treanda®) and other standard chemotherapies are used to treat people with CLL.
Monoclonal antibody therapies for CLL are immune proteins that are made in the lab. They aim for a specific target on the surface of the CLL cells. The antibody attaches to the cell and then the cell dies. This type of therapy is given through a vein by placing a small needle in the arm (called an IV). Monoclonal antibody therapies do cause some side effects. In general, the side effects are milder than the side effects of chemotherapy.
Rituximab (Rituxan®) and alemtuzumab (Campath®) are two of the monoclonal antibody therapies used to treat people with CLL. Rituxan is being studied in clinical trials and is used in combination with chemotherapy. Other new monoclonal antibodies are being studied in clinical trials to treat people with CLL.
Two or more drugs are often combined for CLL treatment. Fludara is often combined with other drugs to treat people with CLL who need drug therapy. For example:
FC - Fludara, Cytoxan FR - Fludara, Rituxan FCR - Fludara, Cytoxan, Rituxan
Treanda combined with other drugs is being studied in clinical trials to treat people with CLL. For example:
Treanda, Rituxan Treanda, lenalidomide (Revlimid®)
Supportive Care
Supportive care is given to prevent or treat CLL symptoms and/or treatment side effects. Supportive care for CLL may include
Antibiotics used to treat infections that are caused by bacteria or fungi. Infections are a risk for CLL patients. The disease and treatment lower the number of infection-fighting white cells in the blood. Patients with repeated infections may also get injections of immunoglobulin.
Blood transfusions or red cell growth factors used to increase the red cell count. Anemia (low numbers of red cells) is a common side effect of chemotherapy. Examples of red cell growth factors are Aranesp® (darbepoetin alfa) and Procrit® (epoetin alfa). Blood cell growth factors may help the patient tolerate the side effects of higher doses of chemotherapy. People with CLL should discuss the risks and benefits of treatment with blood cell growth factors with their doctors.
Growth factors used to improve low white cell counts. CLL-related low blood counts are often corrected by CLL therapy. Sometimes the use of white cell growth factors can help people with CLL who have a long period of low white cell counts after treatment. Examples of white cell growth factors are Neupogen® or Neulasta® (also called "G-CSF") and Leukine® (also called "GM-CSF").
Other Treatments
Radiation therapy is not a common treatment for CLL. This treatment uses x-rays or other high-energy rays to kill cancer cells. It is sometimes used to treat a person with CLL who has an enlarged (swollen) lymph node, spleen or other organ that is blocking the function of a neighboring body part, such as the kidney or the throat.
Splenectomy, surgery to remove the spleen, is used only when a patient's spleen is affected by CLL. CLL cells can enlarge the spleen and cause discomfort in some patients with CLL. Also, an enlarged spleen may lower the patient's blood cell counts to dangerous levels. Splenectomy is helpful for some people with CLL if the spleen is very enlarged as a result of the disease. The operation may improve blood cell counts.
Side Effects of Treatment
CLL patients should talk with the doctor about side effects before they begin treatment. Patients react to CLL treatment in different ways. Sometimes patients have no side effects. Sometimes side effects are mild and last only a short time. Other side effects may be serious and last a long time. Most side effects go away when patients complete treatment.
Some possible side effects of CLL treatment include
Achy feeling Constipation Diarrhea Extreme tiredness Hair loss Infections
Low blood pressure Low platelet count Low red cell count (anemia) Low white cell count Low platelet count Mouth sores Upset stomach and vomiting
Treatment for Relapsed or Refractory CLL
"Relapsed CLL" is the term for CLL that responded to therapy but then stopped responding six or more months after therapy. "Refractory CLL" is the term used to describe CLL that either does not result in a remission (but may be stable) or CLL that gets worse within six months of the last treatment.
People who are treated for relapsed or refractory CLL often have good quality years of remission after more treatment. Treatment options for people with relapsed or refractory CLL are generally the same as treatment for newly diagnosed people. But, some patients who have refractory CLL may have
A short time to CLL cell growth (disease progression) after the first treatment CLL cells with deletion of 17p (a chromosome change)
These patients may have CLL that does not respond to standard drug therapy. They should speak to their doctors about treatment in a clinical trial.
Clinical Trials
Clinical trials are used to study new drugs, new treatments or new uses for approved drugs or treatments. There are a growing number of CLL clinical trials for adults of all ages including newly diagnosed patients, patients with relapsed or refractory CLL and patients with CLL who continue treatment after remission (maintenance). Some specific new drug therapies under study in clinical trials for people with CLL include
Ofatumumab (Arzerra®) - Ofatumumab is an investigational, monoclonal antibody that targets CD20, a key target in CLL therapy because it is expressed on most B cells in people with CLL.
Lumiliximab - This is an antibody that targets CD23 on the surface of CLL cells. It is being studied in clinical trials in combination with fludarabine, cyclophosphamide and rituximab (FCR) to see if it enhances the activity of FCR for the treatment of patients with relapsed CLL.
Flavopiridol - Flavopiridol is being studied in people with high-risk genetic features whose CLL has responded to few, if any standard treatments.
Lenalidomide (Revlimid) - This is an immunomodulatory drug that stimulates a person's own immune system to attack cancer cells. It is being evaluated in CLL trials to determine if lenalidomide given as a
maintenance therapy is safe and effective in further improving the quality and duration of the response to treatment.
Stem cell transplants are also under study in clinical trials. An allogeneic stem cell transplant is a type of stem cell transplant used to treat some diseases. This is a treatment to restore a person's marrow. Allogeneic stem cell transplantation is under study for people with high-risk CLL. It may be a good treatment for some people younger than 55 years who are not doing well with other treatments. The person also needs to have a "matched" stem cell donor.
With an allogeneic stem cell transplant, stem cells from a donor are used. The donor can be a brother or sister. Or the donor can be another person with stem cells that "match" the stem cells of the transplant patient. First, the transplant patient is given high-dose chemotherapy and/or radiation therapy. Then stem cells from the donor are infused into to the transplant patient's blood. An allogeneic stem cell transplantation has a high risk of serious complications. Your doctor will explain the benefits and the risks if transplantation is suggested for you.
Doctors are working to make allogeneic stem cell transplants safer. A type of transplant called a "reduced-intensity transplant" is under study. A reduced-intensity transplant uses lower doses of chemotherapy than a standard allogeneic stem cell transplant. This treatment is also called a nonmyeloablative transplant. Older and sicker patients may be helped by this treatment.
Ask your doctor if treatment in a clinical trial is right for you. You can also call the Information Resource Center for information about clinical trials or use TrialCheck®, the free LLS-supported clinical trials service.
Treatment Response and Follow-Up
People with CLL have a range of responses after treatment. Talk to your doctor about the results of your treatment. Your doctor may use the following terms to talk about your response to treatment:
Remission - No sign of disease; sometimes the terms "complete remission" (or complete response) or "partial remission" (or partial response) are used.
Complete response (CR) - No sign of disease for at least two months after the end of treatment; normal blood counts and hemoglobin greater than 11 g/dL without transfusions; no CLL signs or symptoms.
Partial response (PR) - At least a 50 percent reduction in the number of blood lymphocytes and in lymph node and spleen enlargement; one or more of the following must also be maintained for at least two months: platelets greater than 100,000/ul; hemoglobin greater than 11 g/dL; or a 50 percent improvement over pretreatment red cell or platelet counts without transfusions.
Stable disease - This means the person's CLL is not growing, but the person does not have a complete or partial response.
Progressive disease - The signs of progressive disease are at least one of the following:
An increase of at least 50% in lymphocyte count or other signs of high-risk CLL.
An increase of at least 50% in liver or spleen size or a newly enlarged liver or spleen. An increase of at least 50% in the combined size of at least two lymph nodes, in two exams in a
row, done two weeks apart. New appearance of enlarged lymph nodes.
Follow-Up Care
After CLL treatment, patients need to see their doctors for physical exams and blood tests. Bone marrow tests or FISH may be needed from time to time. The doctor may recommend longer periods of time between follow-up visits if a person continues to be free of CLL signs or symptoms.
Minimal Residual Disease (MRD)
Some people with CLL have a very low level of remaining CLL cells after treatment. The remaining CLL ells are called "minimal residual disease" (MRD). MRD cannot be detected by the usual blood and marrow tests. The tests to detect MRD in people with CLL are "four-color cell flow cytometry" and polymerase chain reaction (PCR). These tests may help the doctor to identify the need for more treatment.
