What to Know About CSF1R Inhibitors

A Class of Drugs Approved to Take on Several Forms of Cancer

In This Article

CSF1R inhibitors, also known as kinase inhibitors, are a class of drug that take on the formation of cancer tumors by binding to tyrosine kinase receptor colony stimulating factor 1 receptors (CSF1R). In doing so, they prevent signaling from specialized cells from the body that become overactive in cancer cases, thereby hindering the progress of the disease.

In turn, this immunosuppressive effect prevents tumors from growing and spreading. While some of these medications have started to be employed in therapy, a number of others of this class are still in clinical trial phases.

Typically taken orally and designed to function alone or alongside other drugs, there are many types of CSF1R inhibitors. For instance, one such drug, Turalio (pexidartinib, also known as CSF1R PLX3397), is approved for use in the treatment of symptomatic tenosynovial giant cell tumor (TGCT), in which benign tumors that grow in membranes and structures associated with joints.

Other drugs of this class, such as Gleevec (imatinib), Sprycel (dasatinib), and Bosulif (bosutinib), may also be for several forms of leukemia (a cancer of the white blood cells) as well as other types of cancer. There are several CSF1R inhibitors approved for use, with others currently undergoing clinical trials.  

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Uses

CSF1R inhibitors target and modulate function of the tyrosine kinase enzyme, which functions as a kind of “off/on” switch for cells. This prevents the kind of activity that can lead to tumor growth. Here’s a breakdown of current FDA-approved uses:

  • Tenosynovial giant cell tumor (TGCT): When initial treatments, such as surgery, are contraindicated or haven’t yielded results, Turalio will be prescribed for TGCT. This is a rare form of cancer characterized by the growth of tumors in and around the joints.  
  • Leukemia: Gleevec, bosutinib, and dasatinib are among the CSF1R inhibitors that are approved by the U.S. Food and Drug Administration (FDA) to take on leukemia or other disorders or cancers of the blood.
  • Gastrointestinal tumors: Given its efficacy in directly preventing tumor growth, CSF1R inhibitors are also indicated for cases of tumor growth within the gastrointestinal system. Again, this treatment is considered when other options, including surgery, are deemed risky or unsuccessful. 
  • Myelodysplastic/myeloproliferative disease: This rare genetic disorder leads to overproduction of white blood cells in the bone marrow; as a result, production of other blood cell types is affected. CSF1R inhibitors may be prescribed to take on this condition, especially in younger patients.
  • Non-small cell lung cancer: Recently, a couple drugs of this class have been approved to take on certain forms of lung cancer.
  • Breast cancer:  Several CSF1R inhibitors, including neratinib (CSF1R HKI-272) and Tykerb (lapatinib) have been approved as therapies for breast cancer.
  • Kidney cancer: Among others, Votrient (pazopanib) and Sutent (sunitinib) have been approved for use in certain cases of kidney or soft tissue cancer.
  • Dermatofibrosarcoma protuberans: Another rarer disorder taken on by Gleevec is this type of cancer, characterized by the growth of tumors just underneath the skin. It’s indicated when surgical removal of the tumors is dangerous, or if the cancer has started to spread.
  • Aggressive systemic mastocytosis: Aggressive cases of this blood disorder are characterized by by an abnormal build-up of mast cells (a type of white blood cell) in different tissues and organs throughout the body. 

Since drugs of this class are able to target specific pathways that promote tumor growth, there’s hope that the drugs in development and undergoing clinical trials will be able to take on a greater range of cancers.

Before Taking

CSF1R inhibitors are typically indicated for cases in which surgery or other treatments to remove tumors are too risky or have not succeeded. Their activity on specific receptors make them a targeted therapy, in contrast to radiation, chemotherapy, or other approaches that can harm cancer and healthy cells alike.

Turalio, for instance, is indicated for TGCT cases that tend to be more severe, impacting mobility, and potentially leading to death. Similarly, Gleevec will be considered when surgery or other methods of taking on dermatofibrosarcoma protuberance have not yielded the desired result.

Precautions and Contraindications

Following diagnosis of a cancer that can be treated using CSF1R inhibitors, the medical team will offer consultation and discuss your treatment options. Many factors need to be weighed before undergoing this therapy.

Notably, there are no outright contraindications for this class of drug; however, other medications or substances can influence their efficacy. Be sure to talk to your doctor about what prescribed or over-the-counter medications as well as any herbs or supplements you’re taking.

Certain patient populations may not be good candidates for CSF1R inhibitors. Factors that are a cause for precaution or even contraindication include:

  • Allergies: Some people may be allergic to CSF1R inhibitors or ingredients used to manufacture them. If you have any known allergies, make sure to let your doctor know.
  • Pregnancy: Administration of CSF1R drugs may harm a developing fetus, so doctors may advise against pregnant women taking them.
  • Liver problems: CSF1R inhibitors are known to have a hepatoxic effect, meaning they can damage the liver. People with a history of liver disease will need to be carefully monitored if given this type of drug, or other treatments should be explored.
  • Cardiac problems: Taking a drug of this class may also be dangerous for people who have heart disease or are at risk for it. 
  • Weakened immune system: Generally speaking, CSF1R limits some immune function, so longer term use may become problematic for people who have other problems with this system.
  • Kidney problems: As patients take CSF1R inhibitors, doctors also need to monitor kidney health closely. Long term use may start to damage these organs.
  • Breastfeeding: Though more research is needed, it’s possible that this class of drug can enter breast milk. As such, doctors may recommend that people taking these drugs stop breastfeeding during the course of treatment.

Other CSF1R Inhibitors

There are a several CSF1R inhibitors that are currently used therapeutically, including:

  • Bosulif (bosutinib)
  • Gleevec (imatinib)
  • Iressa (gefitinib or CSF1R ZD1839)
  • Jakafi (ruxolitinib)
  • Sprycel (dasatinib)
  • Sutent (sunitinib)
  • Tarceva (erlotinib)
  • Turalio (pexidartinib)
  • Tykerb (lapatinib)
  • Votrient (pazopanib)
  • Xalcori (crizotinib)
  • Zelboraf (vemurafenib)

Dosage

When it comes to dosage, it’s important to note that the final word rests with your doctor; they may modify their recommendations based on your case. Given that CSF1R are a class of drug, there also may be differences based on the specific drug you’re taking. Make sure to learn as much as you can about how to safely and properly take your medications.

Here’s a quick breakdown of dosages for some of the more popular CSF1R inhibitors:

  • Gleevec: 400 to 600 milligrams (mg) of Gleevec is indicated for adult patients, with higher doses indicated for more severe cancers. Most often, this is taken in pill form once daily with a meal, with individual pills coming in two strength levels: 100 mg and 400 mg.
  • Turalio: This pill is taken twice a day one hour before or two hours after a meal, for a total of 400 mg a day. Pills should be taken whole and not broken or crushed. Each one contains 200 mg of the active ingredient.
  • Sprycel: Typically, 100 mg a day is the prescribed dose of Sprycel—though this may be boosted to 140 mg for more advanced cases. These pills come in several strengths: 20 mg, 50 mg, 70 mg, 80 mg, 100 mg, and 140 mg. These can be taken with or without a meal.
  • Bosulif: Typically, 400 mg a day of Bosulif is prescribed, though more advanced cases may call for 500 mg a day doses. These are to be taken orally, once a day with food. There are three dosage strengths of these pills: 100, 400, and 500 mg pills.

Keep in mind that the above are FDA-approved recommendations from manufacturers, and your doctor may adjust your daily dosage as necessary.

Modifications

As with any drug, specific dosages may vary based on disease progression, patient’s age, and health status. Generally speaking, older patients may have increased risk of side-effects. Recommendations for modifications include:

  • Gleevec: Typically, 260 mg a day recommended for children above the age of two for chronic leukemia, and 340 mg for newly-diagnosed cases. For those who have trouble swallowing the pills, it can be crushed and added to water or juice for easier consumption. In some cases, doctors may ask patients to boost dosage—up to 800 mg a day—which would then be split into two 400 mg doses (one in the morning and one at night).
  • Turalio: The safety of Turalio use in pediatric patients has not been established, so this drug is typically not prescribed for this population.  
  • Sprycel: In cases where therapeutic effect is not seen, your doctor may find a need to escalate the daily dosage of this drug up to 180 mg.
  • Bosulif: With this drug, doctors may also call for escalation of dosage up to 600 mg a day.

Again, there are many different types of this drug, so make sure you have a solid understanding of what you’re taking and how to take it properly.

How to Take and Store

There is some variation when it comes to individual CSF1R inhibitors; however, these tend to overlap. What should you keep in mind as you’re taking your medication? Here’s a quick breakdown:

  • Meals and dosage: Depending on the specific CSF1R, you may need to either take the medication with or without food. As noted, Bosulif and Gleevec, among others, should be taken with food, while, for instance, Turalio should be taken on an empty stomach. Double check to make sure what you’re taking and how it should be administered.
  • Foods and substances to avoid: Some supplements or foods may hinder the efficacy of CSF1R inhibitors. Notably, avoid eating grapefruit or drinking grapefruit juice.
  • Overdosage: In general, if you’ve found that you’ve taken more than the prescribed amount, you should contact medical help or a poison control center immediately.
  • Missed doses: If you miss a dose, it’s recommended that you simply stick to your schedule and take the next one at the right time. Do not double-up on doses.
  • Storage considerations: Largely, this class of drugs should be stored in their original container at room temperature and safely away from children. If your doctor asks you to end your treatment and there are leftover pills, be sure to take them back to the pharmacy for safe disposal.

Side Effects

There are some variations among individual CSF1R inhibitors, so be sure to talk to your doctor about specific side effects of the drug you’re taking. Largely, however, there’s a great deal of overlap with this class of drugs.

As you’re undergoing this therapy, monitor how you’re feeling and be sure to let your doctor know if anything feels off.

Common

As with any drug, there is a set of more common side-effects that have been observed. These include:

  • Nausea
  • Vomiting
  • Abdominal pain
  • Pain in arms or legs
  • Loss of appetite
  • Weight loss
  • Muscle cramps
  • Pink eye
  • Sweating
  • Itchiness
  • Fatigue
  • Rash
  • Muscle inflammation
  • Diarrhea
  • Hair loss or changes in color

If any of these become difficult to manage, be sure to call your doctor.

Severe

While generally safe, there is a chance of more severe reactions when taking CSF1R inhibitors. These need to be reported immediately as they may constitute medical emergencies.

The potential danger of CSF1R inhibitors is that they can negatively affect liver, kidney, immune, and cardiac function, especially if taken for longer periods of time.

Here’s a quick breakdown of more adverse side-effects seen with this class of medication:

  • Sudden weight gain
  • Swollen hands or feet
  • Shortness of breath
  • Increased urination at night
  • Chest pain
  • Cardiac problems
  • Swelling around eyes
  • Peeling, blistering, or shedding skin
  • Yellowing of skin or eyes
  • Irregular or sped up heart rate
  • Blood in the stool
  • Abdominal pain or bloating
  • Flu-like symptoms
  • Unusual or excessive bleeding or bruising
  • Excessive fatigue
  • Coughing up pink or blood mucus

Warnings and Interactions

While there are no outright contraindications for CSF1R inhibitors, there are a number of drugs and substances that they can interact with, hindering their efficacy. These include:

  • CYP3A metabolizers: Drugs of this class, usually used as antibiotics, include Rifadin (rifampin), among others.
  • CYP3A inhibitors: This class of antiviral or antifungal medication includes Xologel (ketoconazole), Sporanox (itraconazole), nefazodone, Viracept (nelfinavir), Norvir (ritonavir), and Vfend (voriconazole), among others.
  • Drugs metabolized by CYP3A4: Drugs of this class often have a pain attenuating effect and include alfentanil, Sandimmune (cyclosporine), diergotamine, ergotamine, Duragesic (fentanyl), and Jantovin (warfarin) among others.
  • Drugs metabolized by CYP2D6: These drugs include an array of anti-depressants, such as Celexa (citalopram), Lexapro (escitalopram), Prozac (fluoxetine), Paxil (paroxetine), and Zoloft (sertraline). Beta-blocking drugs, such as Sectral (acebutolol), Tenormin (atenolol), and Kerlone (betaxolol) are among others. Some drugs of this class also function as opiates or cardiac drugs.
  • Tylenol (acetaminophen): Over the counter or prescribed acetaminophen may also interact poorly with CSF1R inhibitors.
  • Grapefruit: As noted above, grapefruit can also interact poorly with this class of drug.
  • St. John’s Wort: Use of this herb can also lead to poor interaction with CSF1R inhibitors and should be discontinued during therapy.

As you talk to your doctor about CSF1R inhibitors, it’s absolutely essential that you have a list of what you’re taking and supplements you’re consuming handy.

 

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Article Sources
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