Duvelisib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Duvelisib acts as a strong reversible inhibitor of the isoform gamma and delta of the phosphoinositide3-kinase (PI3K). PI3K plays a very important role in innate and adaptative immunity and the inhibition of the form delta and gamma has been very important for the suppression of immunity. The activity of PI3K gamma and delta is restricted to hematopoietic cells and it is necessary for normal B cell development. In lymphomas, the activation of PI3K is enlarged to promote unlimited growth and survival. Hence, inhibition of PI3K can provide inhibition of the signaling from BCR, inhibition of a cytokine signaling from the microenvironment, and enhancement of anti-tumor immunity. The specific mechanism of these PI3K inhibitors is further described as follows: -BCR activates signaling pathways after antigen engagement and it is also critical for the physiologic life of the lymphocytes and neoplastic lymphomas. In CLL, BCR reacts to auto- and exo-antigens to promote clonal expansion. This sustained presence of BCR activates delta PI3K producing a pro-survival pathway of the neoplastic cells which already present a higher activity of PI3K. Thus, the blockade of PI3K will limit the activity of BCR and the driven physiology of the lymphoma. -The inhibition of PI3K can also inhibit paracrine and autocrine pro-survival signals mediated by adhesion molecules, chemokines, and soluble factors. This activity is attained due to the fact that several downstream signals convey on PI3K. -It has been reported that the inactivation of PI3K produces a significant resistance to tumorigenesis. This data suggests that inhibition of PI3K can facilitate the recognition and elimination of tumor cells. In summary, duvelisib inhibits the isoform delta of PI3K which is necessary for cell proliferation and survival, and the isoform gamma which is critical for cytokine signaling and the pro-inflammatory response.

Preclinical data showed that duvelisib presents cytotoxic actions at micromolar doses and antagonizes the activation of downstream signaling even in the presence of the mutation BTK C481S, which allows for the treatment of patients resistant to ibrutinib. In clinical trials, duvelisib was compared to ofatumumab in patients with chronic lymphocytic leukemia or small lymphocytic leukemia. These trials reported a median progression-free survival of 16.4 months and an overall response rate of 78% which were almost 2-fold what was reported for ofatumumab. In clinical trials of follicular lymphoma, duvelisib presented an overall response rate of 42% from which almost all the patients observed a partial response. Of the responding patients, 43% maintained the response for at least 6 months and 17% for at least 12 months.

Indications

  • Duvelisib is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) after at least two prior therapies. CLL is a cancer of the blood stem cells which are the blood cells that can develop into different types of cells. In leukemia, there is an overproduction of cells that are abnormal and do not mature into blood cells thus, they just crowd out normal cells and impair their normal function. In lymphocyte leukemia, abnormal cell growth is observed in the lymphoid cells which are the type of blood cells that mature into lymphocytes. CLL is a type of lymphocytic leukemia that develops slowly over months or years. The SLL is a very similar disease to the CLL and these terms are usually referred to interchangeably. The only difference between these two diseases is that in CLL the cells are found mostly in the blood and bone marrow while in SLL, the cells are mainly found in the lymph nodes. As well, duvelisib obtained accelerated approval for the treatment of adult patients with relapsed or refractory follicular lymphoma after at least two prior systemic therapies. This approval is still under the status of continued approval and it is restrained to confirmatory trials. The follicular lymphoma is a B-cell lymphoma that clusters in the lymph nodes or other tissues.
  • Treatment of mature B cell malignancies Copiktra monotherapy is indicated for the treatment of adult patients with Relapsed or refractory chronic lymphocytic leukemia (CLL) after at least two prior therapies, Follicular lymphoma (FL) that is refractory to at least two prior systemic therapies.
  • Duvelisib is indicated for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adult patients who have trialed at least two prior therapies.
  • Duvelisib is an inhibitor of phosphatidylinositol 3-kinase delta and gamma used to treat relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.
  • Refractory Small Lymphocytic Lymphoma
  • Relapsed Chronic Lymphocytic Leukemia
  • Refractory Chronic Lymphocytic Leukemia (CLL)
  • Relapsed Small Lymphocytic Lymphoma

Contraindications

  • a bad infection
  • low levels of a type of white blood cell called neutrophils
  • a type of inflammation of the lung called interstitial pneumonitis
  • inflammation of the large intestine
  • abnormal liver function tests
  • pregnancy
  • a patient who is producing milk and breastfeeding

Dosage

Strengths: 15 mg; 25 mg

Chronic Lymphocytic Leukemia

  • 25 mg orally 2 times a day in 28-day cycles until unacceptable toxicity or progressive disease
  • If a dose is missed by fewer than 6 hours, take the missed dose right away and take the next dose as usual. If a dose is missed by more than 6 hours, wait and take the next dose at the usual time.
  • Provide prophylaxis for Pneumocystis jirovecii (PJP) during therapy with this drug.
  • Withhold therapy in patients with suspected PJP of any Grade and discontinue if PJP is confirmed.
  • Consider prophylactic antivirals during therapy to prevent cytomegalovirus (CMV) infection/reactivation.

Dose Adjustments

DOSE MODIFICATION LEVELS:

  • Initial dose: 25 mg orally 2 times a day
  • Dose reduction: 15 mg orally 2 times a day
  • Subsequent dose modification: Discontinue therapy if the patient is unable to tolerate 15 mg orally 2 times a day.

Nonhematologic Adverse Reactions:
INFECTION:

  • Grade 3 or greater infection: Withhold therapy until resolved; resume at the same or reduced dose.
  • CMV infection or viremia (positive PCR or antigen test): Withhold therapy until resolved; resume at the same or reduced dose; if therapy is resumed, monitor for CMV reactivation (by PCR or antigen test) monthly.
  • Pneumocystis jiroveci pneumonia (PJP): For suspected PJP, withhold therapy until evaluated; for confirmed PJP, discontinue therapy.

NON-INFECTIOUS DIARRHEA OR COLITIS:

  • Mild/moderate diarrhea (Grade 1 or 2, up to 6 stools per day over baseline) and responsive to antidiarrheal agents, OR asymptomatic (Grade 1) colitis: Maintain current dose; initiate antidiarrheals if needed; monitor weekly until resolved.
  • Mild/moderate diarrhea (Grade 1 or 2, up to 6 stools per day over baseline) and unresponsive to antidiarrheals: Withhold therapy until resolved; initiate enteric-acting steroids (e.g., budesonide); monitor weekly until resolved; resume at a reduced dose.
  • Abdominal pain, stool with mucus or blood, change in bowel habits, peritoneal signs, OR severe diarrhea (Grade 3, greater than 6 stools per day over baseline): Withhold therapy until resolved; initiate enteric acting steroids (e.g., budesonide) or systemic steroids; monitor weekly until resolved; resume at a reduced dose. For life-threatening recurrent Grade 3 diarrhea or recurrent colitis of any Grade, discontinue therapy.

CUTANEOUS REACTIONS:

  • Grade 1 to 2: Maintain dose; initiate emollients, antihistamines, or topical steroids; monitor closely.
  • Grade 3: Withhold therapy until resolved; initiate emollients, antihistamines, or topical steroids; monitor weekly until resolved; resume at a reduced dose. If a severe cutaneous reaction does not improve, worsens, recurs, or becomes life-threatening, discontinue therapy.
  • SJS, TEN, DRESS (any Grade): Discontinue therapy.

PNEUMONITIS WITHOUT SUSPECTED INFECTIOUS CAUSE:

  • Moderate (Grade 2) symptomatic pneumonitis: Withhold therapy; initiate systemic steroids; if pneumonitis recovers to Grade 0 or 1, resume therapy at a reduced dose; if non-infectious pneumonitis recurs or the patient does not respond to steroid therapy, discontinue this drug.
  • Severe (Grade 3) or life-threatening pneumonitis: Discontinue therapy; initiate systemic steroids.

ALT/AST ELEVATION:

  • Grade 2 (3 to 5 x upper limit of normal [ULN]): Maintain dose; monitor weekly until recovery to less than 3 x ULN.
  • Grade 3 (greater than 5 to 20 x ULN: Withhold therapy and monitor weekly until recovery to less than 3 x ULN; resume at the same dose (first occurrence) or reduce dose for subsequent occurrences.
  • Grade 4 (greater than 20 x ULN: Discontinue therapy.

Hematologic Adverse Reactions:
NEUTROPENIA:

  • Absolute neutrophil count (ANC) 0.5 to 1 Gi/L: Maintain dose; monitor ANC weekly.
  • ANC less than 0.5 Gi/L: Withhold therapy; monitor ANC until greater than 0.5 Gi/L; resume at the same dose (first occurrence) or reduce dose for subsequent occurrences.

THROMBOCYTOPENIA:

  • Grade 3 (platelet count 25 to less than 50 Gi/L with Grade 1 bleeding: Maintain dose; monitor platelet counts weekly.
  • Grade 3 (platelet count 25 to less than 50 Gi/L with Grade 2 bleeding or Grade 4 (platelet count less than 25 Gi/L): Withhold therapy; monitor platelet count until 25 Gi/L or greater and resolution of bleeding; resume at the same dose (first occurrence) or reduce dose for subsequent occurrences.

Dose Modification for Concomitant Use with CYP450 3A4 Inhibitors:

  • When given with strong CYP450 3A4 inhibitors (e.g., ketoconazole), reduce the dose of this drug to 15 mg orally 2 times a day.

Administration advice:

  • This drug may be taken with or without food.
  • Capsules should be swallowed whole, not opened, broken, or chewed.

Side Effects

The Most Common

  • nausea
  • vomiting
  • constipation
  • tiredness
  • headache
  • muscle or joint pain
  • yellow eyes or skin;
  • abdominal pain;
  • unexplained bruising or bleeding;
  • loss of appetite;
  • yellow or brown-colored urine;
  • pale stools;
  • pain in the upper right part of the stomach
  • low blood cell counts;
  • bone pain, muscle pain;
  • fever, cough, tiredness; or
  • cold symptoms such as stuffy nose, sneezing, and sore throat.

More Common

  • abdominal pain
  • appetite change
  • back pain
  • blurred vision
  • constipation
  • diarrhea
  • dizziness
  • dry mouth
  • excessive sweating
  • headache
  • heartburn
  • joint pain
  • muscle aches and pain
  • nausea
  • pain in the arms and legs
  • skin redness
  • tiredness
  • vomiting
  • weight changes
  • chest pain
  • fainting
  • fever
  • high blood pressure

Rare

  • mouth sores
  • numbness, tingling, muscle weakness, and pain
  • rash
  • ringing, buzzing, hissing, or clicking sounds in the ears
  • shortness of breath
  • signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
  • signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
  • signs of depression (e.g., poor concentration, changes in weight, changes in sleep, decreased interest in activities, thoughts of suicide)
  • signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
  • swollen hands, feet, or joints
  • symptoms of fluid around the lungs (e.g., chest pain, difficult or painful breathing, cough)
  • symptoms of irregular heartbeat (e.g., chest pain, dizziness, rapid, pounding heartbeat, shortness of breath)
  • symptoms of a lung infection (LRTI) (e.g., shortness of breath, cough, chest pain)
  • symptoms of skin cancer (e.g., skin sore, wart, or bump that does not heal)
  • symptoms of a urinary tract infection (e.g., pain when urinating, urinating more often than usual, low back or flank pain)
  • symptoms of fluid around the lungs (e.g., chest pain, painful breathing, cough)
  • waking up in the night to urinate
  • signs of bleeding in the stomach (e.g., bloody, black, or tarry stools; spitting up of blood; vomiting blood or material that looks like coffee grounds)
  • signs of a serious allergic reaction (e.g., abdominal cramps, difficulty breathing, nausea and vomiting, or swelling of the face and throat)

Drug Interaction

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Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus. Verify negative pregnancy status in females of reproductive potential prior to initiating therapy. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during therapy and for at least one month after the last dose.

Lactation

This drug may harm a nursing child. Women should not breastfeed while taking this drug and for at least one month after. No information is available on the use of this drug during breastfeeding. Because it is 98% bound to plasma proteins, the amount in milk is likely to be low; however, because of its potential toxicity in the breastfed infant, the manufacturer recommends that breastfeeding be discontinued.

How should this medicine be used?

Duvelisib comes as a capsule to take by mouth. It is usually taken twice daily with or without food. Take duvelisib at around the same times every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take duvelisib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the capsule whole; do not open, chew, or break them.

Your doctor may decrease your dose of duvelisib or tell you to stop taking the medication for a time or permanently if you experience serious side effects during your treatment. This depends on how well the medication works for you and the side effects you experience. Talk to your doctor about how you are feeling during your treatment. Continue to take duvelisib even if you feel well. Do not stop taking duvelisib without talking to your doctor.

What special precautions should I follow?

Before taking duvelisib,

  • tell your doctor and pharmacist if you are allergic to duvelisib, any other medications, or any of the ingredients in duvelisib capsules. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take while taking duvelisib. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • The following nonprescription or herbal products may interact with duvelisib: St. John’s wort. Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking duvelisib. Do not start any of these medications while taking duvelisib without discussing it with your healthcare provider.
  • tell your doctor if you have or have ever had liver disease.
  • tell your doctor if you are pregnant or plan to become pregnant. You must have a pregnancy test before you start taking duvelisib. You should not become pregnant during your treatment with duvelisib. If you are female, you should use birth control to prevent pregnancy during your treatment with duvelisib and at least 1 month after your final dose. If you are a male and your partner can become pregnant, you should use effective birth control during your treatment and for 1 month after your final dose. If you or your partner become pregnant while taking duvelisib, call your doctor immediately. Duvelisib may harm the fetus.
  • tell your doctor if you are breastfeeding. You should not breastfeed while you are taking duvelisib and for at least 1 month after your final dose.

References

  1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf
  2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211155s001lbl.pdf
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Duvelisib
  4. https://www.cancer.gov/about-cancer/treatment/drugs/duvelisib
  5. https://www.webmd.com/drugs/2/drug-176153/duvelisib-oral/details/list-contraindications
  6. https://en.wikipedia.org/wiki/Duvelisib
  7. https://go.drugbank.com/drugs/DB11952
  8. https://medlineplus.gov/druginfo/meds/a618056.html
  9. https://www.drugs.com/mtm/duvelisib.html
  10. ChemIDplus Chemical Information Classification
  11. CompTox Chemicals Dashboard Chemical Lists
  12. 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]isoquinolin-1(2H)-one
    8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]isoquinolin-1(2H)-one
  13. 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone
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  15. Guide to Pharmacology Target Classification
  16. PubChem
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