Rare Disease Basics

Rare Diseases

What is Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL)?

Acute lymphoblastic leukemia (ALL) is a fast-growing malignant disorder resulting from proliferation of white blood cells that fail to mature and accumulate in the bone marrow, destroying and replacing cells that produce normal blood cells. Prognosis declines with increasing age and is most unfavorable when the Philadelphia chromosome (Ph) is present.

What causes Ph+ ALL?

Changes in chromosomes (genetic material) are a major cause of abnormal genetic conditions in humans. If a change involves a translocation, part of a chromosome breaks off and attaches to another chromosome. The Philadelphia chromosome results from a reciprocal translocation between chromosomes 9 and 22 in which a gene segment on chromosome 9 is inserted into one of several regions of a gene on chromosome 22. The new gene resulting from this translocation produces an abnormal protein that adversely impacts normal cellular processes, resulting in an increased proliferation of leukemic cells.

What is Myelodysplastic/Myeloproliferative disease (MDS/MPD)?

The myelodysplastic syndromes (MDS) are a diverse collection of blood disorders. characterized by an ineffective production of blood cells. The myeloproliferative diseases (MPDs) are a group of diseases of the bone marrow in which excess cells are produced. Myelodysplastic/myeloproliferative overlap disorders (MDS/MPD) are malignant stem cell disorders that have both dysplastic and proliferative features at the time of initial presentation, resulting in increased numbers of immature cells in the bone marrow and a decrease in mature functional cells in the blood.

What causes MDS/MPD?

While patients with MDS/MPD lack the Philadelphia chromosome that is common to chronic myeloid leukemia (CML), chromosomal damage is common in patients with this disease, including gene rearrangements involving the platelet-derived growth factor receptor gene known as PDGFR. The new gene resulting from this kind of rearrangement produces an abnormal protein that adversely impacts normal cellular processes, causing cells to multiply out of control.

What is aggressive systemic mastocytosis (ASM)?

Aggressive systemic mastocytosis (ASM) is a myeloproliferative disorder characterized by the abnormal growth, proliferation, and accumulation of mast cells in one or more organs that can, in some cases, lead to organ failure. There is usually severe involvement of the bone marrow, liver, spleen, and lymphatic system. Mast cells are produced in the bone marrow and contain chemical mediators, like histamine, that are released in response to inflammatory and allergenic events.

What causes ASM?

Changes in chromosomes (genetic material) are a major cause of abnormal genetic conditions in humans. If the change involves a mutation in a gene, then the protein produced by the gene will usually not function as intended. If the change involves a deletion within a gene, there is a loss of genetic information, resulting in a shorter than normal protein that will also usually not function as intended. ASM is associated with a specific mutation within the c-Kit gene on chromosome 4 or a deletion within the chromosome that causes abnormal activation of the platelet-derived growth factor receptor gene, known as PDGFR. This new gene makes an abnormal protein that adversely impacts normal cellular processes, causing cells to multiply out of control.

What is hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL)?

Hypereosinophilic syndrome (HES) is a blood disorder characterized by unexplained, higher than normal levels of eosinophils, a type of white blood cell, and evidence of organ dysfunction due to eosinophilic tissue infiltration. In some cases, it can additionally be characterized by elevated levels of immature mast cells in the bone marrow and mast cell products in the blood. When associated with chromosomal abnormalities, the disease is then called chronic eosinophilic leukemia (CEL).

What causes HES/CEL?

An overproduction of eosinophils in the bone marrow with migration into the blood stream and various organs are upstream events associated with the disease.  Changes in chromosomes (genetic material) associated with HES/CEL usually involve translocations of the platelet-derived growth factor receptor gene known as PDGFR. They are a major cause of abnormal genetic conditions in humans. If a change involves a translocation, part of a chromosome breaks off and attaches to another chromosome. Adjacent to the PDGFR gene are a number of genes important in the growth and maturation of eosinophils. The normal function of these genes may be adversely impacted by the PDGFR translocation process, causing the unexplained eosinophilia.

What is dermatofibrosarcoma protuberans (DFSP)?

Dermatofibrosarcoma protuberans (DFSP) is a locally aggressive cutaneous tumor of intermediate malignancy that is characterized by slow infiltrative growth and a strong tendency toward local recurrence after surgery.

What causes DFSP?

Changes in chromosomes (genetic material) are a major cause of abnormal genetic conditions in humans. If a change involves a translocation, part of a chromosome breaks off and attaches to another chromosome. In rare cases, the broken parts can attach to themselves forming ring structures. Chromosomal translocations and/or ring chromosomes that fuse the collagen gene on chromosome 17 to the platelet-derived growth factor gene, known as PDGFR, on chromosome 22 are present in nearly all cases of DFSP. Abnormal activation of the platelet-derived growth factor receptor gene produces an abnormal protein that adversely impacts normal cellular processes, causing cells to multiply out of control.

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Side effects

Almost all people taking GLEEVEC experience side effects. Be sure to talk to your oncologist and/or healthcare professional about any GLEEVEC side effects you are experiencing.

Some serious side effects include:

  • Severe fluid retention (holding water), which can cause swelling around the eyes or swelling of the lower legs, lungs, and heart (reported in 9%-13.1% of patients); fatal in rare cases
  • Increased pressure in the heart or brain; fatal in rare cases
  • Low levels of certain blood cells
  • Heart failure
  • Liver problems
  • Hemorrhage (abnormal bleeding); reported in 5%-12.9% of patients in clinical trials
  • Skin blistering
  • Low levels of thyroid hormone

Some common side effects are:

  • Fluid retention (holding water)
  • Muscle cramps or pain and bone pain
  • Abdominal pain
  • Vomiting
  • Diarrhea
  • Decreased hemoglobin (decrease in blood cells which carry oxygen)
  • Nausea
  • Fatigue
  • Skin reactions, some severe
  • Anorexia (loss of appetite)

Supportive care may help reduce the severity of some side effects, whereas others require discontinuation or dosage adjustment. Don't stop taking your medication or change your dose without talking to your oncologist.

GLEEVEC can cause harm to the unborn child when administered to a pregnant woman. Women should be aware of the potential harm to the fetus. Be sure to inform your doctor if you are or think you may be pregnant. You should not breastfeed while taking GLEEVEC.

Side effects

What it feels like

How your doctor may manage it

Swelling and fluid retention

Swollen legs or feet and swelling around the eyes. Fluid retention can appear as quick weight gain or swelling in your lower legs or other parts of your body. Fluid retention can be serious or even life threatening

  • Regular checkups to monitor your weight
  • Prescribe a topical steroid cream to reduce the swelling around your eyes
  • Tell you to limit your salt intake
  • Prescribe a diuretic (a medicine to help your body get rid of extra fluids)
  • Decrease dose of GLEEVEC

Skin reactions, some severe (including erythema muliforme and Stevens-Johnson syndrome)

Scaly skin; red itchy bumps on skin. Flu-like symptoms followed by painful red or purplish rash

  • Recommend an over-the-counter (OTC) antihistamine
  • Prescribe a corticosteroid or stronger antihistamine
  • Painkillers, sedatives, antibiotics for secondary infections
  • May interrupt therapy and resume at a lower dose

Nausea and vomiting

Feeling queasy or like you have to throw up.You may also feel like you have indigestion

  • Recommend taking GLEEVEC with a meal and a large glass of water. (If you have been instructed not to take GLEEVEC with meals, contact your doctor before changing your dose to mealtimes.)
  • Recommend OTC medications
  • If you are taking your GLEEVEC once a day, talk to your doctor about possibly dividing the dose in half and taking it twice a day

Muscle cramps

Pain or spasms in the legs, feet, or calves

  • Recommend an OTC pain reliever like ibuprofen
  • Recommend a prescription pain reliever
  • Recommend calcium and magnesium supplements

Muscle and bone pain

Whole-body ache; twitching or burning muscles

  • Recommend an OTC pain reliever like ibuprofen
  • Recommend a prescription pain reliever

Diarrhea

More bowel movements; loose stools

  • Recommend an OTC medication

Important information about GLEEVEC® (imatinib mesylate)

GLEEVEC® (imatinib mesylate) is available only by prescription.

GLEEVEC® Indications

GLEEVEC® (imatinib mesylate) tablets are indicated for:

  • Newly diagnosed adult and pediatric patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML) in the chronic phase
  • Patients with Ph+ CML in blast crisis (BC), accelerated phase (AP), or in the chronic phase (CP) after failure of interferon-alpha therapy
  • Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia (Ph+ ALL)
  • Pediatric patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy
  • Adult patients with myelodysplastic/myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements
  • Adult patients with aggressive systemic mastocytosis (ASM) without the D816V c-KIT mutation or with c-KIT mutational status unknown
  • Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown
  • Adult patients with unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans (DFSP)
  • Patients with KIT (CD117)-positive gastrointestinal stromal tumors (GISTs) that are cancerous, cannot be surgically removed, and/or have spread to other parts of the body
  • Adult patients after surgery who have had their KIT (CD117)-positive GISTs completely removed

SAFETY: Important product information (Please see accompanying full Prescribing Information)

Who should NOT take GLEEVEC

  • Women who are or could be pregnant. Harm to the unborn child can occur when administered to pregnant women. Therefore, women should not become pregnant and should be advised of the potential risk to the unborn child if GLEEVEC is used during pregnancy
  • Women who are breastfeeding because of the potential for serious adverse reactions in nursing infants

Sexually active females should use highly effective birth control while taking GLEEVEC.

Be sure to talk to your doctor and/or healthcare professional about these issues before taking GLEEVEC.

Warnings and precautions

  • GLEEVEC is often associated with edema (swelling) and serious fluid retention (holding water). It is important that patients be weighed and monitored regularly for signs and symptoms of serious fluid retention or unexpected weight gain. Patients experiencing unexpected, rapid weight gain should speak to their doctor about appropriate supportive care treatment. Studies have shown that edema tended to occur more often among patients who are 65 and older or those taking higher doses of GLEEVEC. If you experience severe fluid retention, your doctor may treat you with diuretics and may stop your GLEEVEC treatment until the fluid retention has been managed. Treatment can be returned as appropriate depending on the initial severity of the event
  • Cytopenias (reduction or lack of certain cell elements in blood circulation) have occurred. Your doctor will test your blood weekly for the first month, biweekly for the second month, and periodically thereafter. In most cases, your doctor will reduce or interrupt your GLEEVEC therapy; in rare cases, if the cytopenia is severe, your doctor may discontinue treatment
  • Severe congestive heart failure (impaired ability of the heart to pump blood) and left ventricular dysfunction (impaired functioning of the left side of the heart) have been reported, particularly in patients with other health issues and risk factors. Patients with heart disease or risk factors for heart disease or history of renal failure will be monitored and treated for the condition
  • Severe liver problems (hepatotoxicity) may occur. Cases of fatal liver failure and severe liver injury requiring liver transplants have been reported with both short-term and long-term use of GLEEVEC. Your doctor will check your liver function before beginning treatment and continue to monitor liver function as needed. If you experience severe liver problems, your doctor may stop your treatment with GLEEVEC until the liver problem has been managed
  • Bleeding may occur. Severe gastrointestinal (GI) bleeding has been reported in patients with Ph+ CML and KIT+ GIST. GI tumor sites may be the cause of this bleeding; therefore, GI symptoms should be monitored at the start of treatment
  • GI perforation (small holes or tears in the wall of the stomach or intestine), in some cases fatal, has been reported
  • In patients with hypereosinophilic syndrome (a condition with increased eosinophils, which are a type of white blood cell), e.g., HES, MDS/MPD, or ASM and heart involvement, cases of heart disease have been associated with the initiation of GLEEVEC therapy. Speak to your doctor regarding appropriate supportive care or discontinuing GLEEVEC
  • Skin reactions, such as fluid-filled blisters, have been reported with the use of GLEEVEC
  • Clinical cases of hypothyroidism (reduction in thyroid hormones) have been reported in patients taking levothyroxine replacement during treatment with GLEEVEC. Your doctor should closely monitor your thyroid hormone levels
  • Long-term use may result in potential liver, kidney, and/or heart toxicities. Immune system suppression may also result from long-term use
  • GLEEVEC can cause harm to the unborn child when administered to a pregnant woman. Women should be aware of the potential harm to the fetus. Be sure to inform your doctor if you are or think you may be pregnant. You should not breastfeed while taking GLEEVEC
  • Growth retardation (slowing of growth) has been reported in children taking GLEEVEC. The long-term effects of extended treatment with GLEEVEC on growth in children are unknown. Growth retardation may be monitored in children receiving treatment
  • Cases of tumor lysis syndrome (TLS), which refers to an electrolyte disturbance caused by the breakdown of tumor cells, have been reported and can be life threatening in some cases. The patients at risk of TLS are those who have a higher number of tumor cells and whose tumors are fast growing before beginning therapy. Your doctor should monitor you closely and take appropriate precautions. Correction of clinically significant dehydration and treatment of high uric acid levels are recommended prior to initiation of GLEEVEC
  • Motor vehicle accidents involving patients receiving GLEEVEC have been reported. Patients should be advised that they may experience undesirable effects such as dizziness, blurred vision, or drowsiness during treatment with GLEEVEC. Caution should be recommended when driving a car or operating machinery

Additional important safety information

The following serious side effects have been reported by patients taking GLEEVEC:

  • Severe fluid retention (holding water), which can cause swelling around the eyes or swelling of the lower legs, lungs, and heart; fatal in rare cases
  • Increased pressure in the heart or brain; fatal in rare cases
  • Low levels of certain blood cells
  • Heart failure
  • Liver problems
  • Hemorrhage (abnormal bleeding)
  • Skin blistering
  • Low levels of thyroid hormone

Your doctor will check you closely for any side effects to stop more serious complications from occurring. Patients with heart disease or risk factors for heart failure should also be monitored carefully.

GLEEVEC is sometimes associated with stomach or intestinal irritation. GLEEVEC should be taken with food and a large glass of water to minimize this problem. There have been rare reports, including deaths, of stomach or intestinal perforation (a small hole or tear).

If you are experiencing any of the above-mentioned side effects, please be sure to speak with your doctor immediately.

Common side effects of GLEEVEC

Almost all patients treated with GLEEVEC experience side effects at some time. Most side effects are mild to moderate in severity. Some common side effects that you may experience include:

  • Fluid retention (holding water)
  • Muscle cramps, pain, or bone pain
  • Abdominal pain
  • Anorexia (loss of appetite)
  • Vomiting
  • Diarrhea
  • Decreased hemoglobin (decrease in blood cells which carry oxygen)
  • Hemorrhage (abnormal bleeding)
  • Nausea
  • Fatigue
  • Rash

If you are experiencing any of the above-mentioned side effects, please be sure to speak with your doctor immediately.

The severity of some side effects may be reduced with the help of other medicines and advice from your doctor, while others may require stopping GLEEVEC therapy for a while or changing the dose. However, in some cases, GLEEVEC therapy may need to be discontinued.

Tell your doctor if you have a history of heart disease or risk factors for heart disease or if you experience side effects, including fever, shortness of breath, blood in your stools, jaundice (yellowing of the skin and/or eyes), sudden weight gain, or symptoms of heart failure during therapy with GLEEVEC.

After the approval of GLEEVEC, the following adverse events have been reported in patients treated with GLEEVEC: compression of the heart due to increased fluid, swelling of the brain, GI perforation (holes in the stomach or intestine), and sudden lung failure. These events, including some fatalities, may or may not have been drug related.

Take GLEEVEC exactly as prescribed. Do not change your dose or stop taking GLEEVEC unless you are told to do so by your doctor. If you miss a dose, take your dose as soon as possible, unless it is almost time for your next dose. In this case, your missed dose should not be taken. A double dose should not be taken to make up for any missed dose. You should take GLEEVEC with a meal and a large glass of water.

Do not take any other medications without talking to your doctor or pharmacist first, including over-the-counter medications such as Tylenol® (acetaminophen); herbal products (St. John's wort, Hypericum perforatum); or prescription medications including Coumadin® (warfarin sodium); rifampin; erythromycin; metoprolol; ketoconazole; and Dilantin® (phenytoin). Taking these with GLEEVEC may affect how they work, or affect how GLEEVEC works.

You should also tell your doctor if you are taking or plan to take iron supplements. Patients should also avoid grapefruit juice and other foods that may affect how GLEEVEC works.

Tylenol (acetaminophen) is a registered trademark of McNeil Consumer & Specialty Pharmaceuticals, a division of McNeil PPC, Inc. Coumadin (warfarin sodium) is a registered trademark of Bristol-Myers Squibb Company. Dilantin (phenytoin) is a registered trademark of Parke-Davis, a division of Pfizer Inc.

Please see accompanying full Prescribing Information, which includes a more complete discussion of the risks associated with GLEEVEC.

You are encouraged to report negative side effects of prescription drugs to the FDA.  Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.