Duvelisib – Uses, Dosage, Side Effects, Interaction

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.

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

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.

References