Ibrutinib represents a major advance in the treatment of previously treated chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), having achieved dramatic and sometimes durable responses in both diseases. Although ibrutinib is approved by the US Food and Drug Administration for both CLL and MCL, judging by the show of hands at the Oncology Nursing Society 39th Annual Congress, the majority of oncology nurses have not yet had experience with it.
“Research suggests that this highly active oral therapy changes the rates of remission, and the drug is life-saving for many patients,” said Gretchen McNally, PhD, ANP-BC in hematology/oncology, at James Cancer Center in Columbus, Ohio. The effect on survival is not yet known.
Ibrutinib is a first-in-class small-molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is part of the B-cell signaling pathway, and inhibition of this pathway leads to cell death. The drug is administered orally once a day and has a half-life of 4 to 6 hours.
CLL Experience In a phase 1b/2 trial of 48 previously treated patients, ibrutinib achieved dramatic shrinkage of lymph nodes and spleen. However, the lymphocytes migrate from the tumor into the peripheral blood, causing lymphocytosis. “At first the white blood cell counts skyrocket,” McNally told listeners.
“It is important to educate patients that lymphocytosis is expected and does not signal disease progression. Not all CLL patients experience lymphocytosis; it tends to occur in patients with non-bulky disease,” she told listeners.
Ibrutinib is also associated with diarrhea in more than 60% of CLL patients, which usually is manageable with antidiarrheal medication. If severe diarrhea occurs, perform lab tests for electrolyte abnormalities and instruct patients to stay hydrated. Other potential adverse events include infections, fatigue, and musculoskeletal complaints, she said.
The majority of adverse events reported in CLL were grades 1 and 2. The most common grade 3 or 4 nonhematologic adverse events were pneumonia, hypertension, and atrial fibrillation.
Hematologic adverse events were mostly grades 1 and 2; about 34% of patients had grade 3 neutropenia.
Hyperuricemia occurred in 40% of patients, which led to use of allopurinol for the first 4-week cycle. If patients develop rash on allopurinol, stop the allopurinol and determine whether the rash was due to ibrutinib or allopurinol, she continued.
MCL Experience In an open-label, multicenter, single-arm phase 2 trial of 111 heavily pretreated patients, about one-third of the patients developed lymphocytosis. Unlike in CLL, the onset of lymphocytosis occurred during the first few weeks of treatment and typically resolved by a median of 8 weeks, although some patients developed severe lymphocytosis.
Adverse events were similar to those reported in the CLL study and were mostly grades 1 and 2.
The most common grades 3 and 4 nonhematologic events (≥5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Hyperuricemia can also develop. Myelosuppression is similar to what is seen in CLL.
Nurse’s Role “Nurses are on the front lines for adverse events. We see patients weekly for the first cycle when they are most vulnerable to side effects. Then we see them monthly [during] cycles 2 to 6; after that, we see them every 3 months,” McNally explained.
Bleeding events can occur, and patients on anticoagulants are at increased risk of hemorrhage. This effect is not well understood, she said.
“Use your clinical judgment. At Ohio State, we don’t allow patients on anticoagulants to take ibrutinib. For minor surgical procedures such as tooth extraction, we hold ibrutinib for 3 days before and 3 days after. For major surgery, we hold the drug for a week before and a week after,” McNally continued.
“Patients are understandably nervous about withholding ibrutinib for 2 weeks, but they need to understand that the risk of bleeding outweighs the benefit,” she said. “When they withhold ibrutinib, the lymph nodes may swell, but they should be told that this will resolve when they restart the medication.”
Grade 3 or higher infections occurred in 35% of CLL and 25% of MCL patients. Monitor patients and treat them appropriately, she advised.
At Ohio State, antiviral prophylaxis is used in most patients, and antibiotic and antifungal prophylaxis is instituted on an individual basis. During flu season patients are given intravenous immunoglobulin.
Myelosuppression occurred in at least one-third of patients. Blood counts should be monitored monthly, and at each visit patients should undergo lab tests for CBC, LFT, LDH, and uric acid.
Fatal and severe cases of renal toxicity have been reported in patients taking ibrutinib. Nurses should measure serum creatinine and encourage their patients to maintain adequate hydration. Do not give ibrutinib to patients with baseline hepatic impairment.
Ibrutinib increases the risk of developing second primary malignancies (mainly skin cancers), which have been reported in 10% of CLL patients and 5% of MCL patients.
Patients taking ibrutinib should not become pregnant, and breastfeeding is unwise, she said.
With the shift from intravenous to oral chemotherapy, patients have the extra burden of making sure to take their medications. “There is no way to double-check whether patients are adherent, but drugs don’t work in patients who don’t take them,” she said.
“For once-daily dosing of ibrutinib, patients should be encouraged to take the drug at the same time each day and swallow the capsules whole. If they forget a dose, they can take it later the same day and return to the normal schedule the next day,” she continued.
Interrupt therapy for any grade 3 or 4 toxicity. Once toxicity resolves to grade 1 or baseline, restart ibrutinib at the initial dose; if the toxicity recurs, reduce the dose by 1 capsule. If toxicities persist following 2 dose reductions, the drug needs to be discontinued.
Ibrutinib is metabolized by CYP3A. Therefore, avoid use of strong or moderate CYP3A inhibitors if possible. If the patient must use a strong CYP3A inhibitor, it should be used short term with close monitoring. With strong or moderate CYP3A inhibitors, closely monitor the patient for signs of ibrutinib toxicity.
CYP3A inducers decrease ibrutinib concentration 10-fold, and these drugs should be avoided while on therapy. Consider alternatives and use only over the short term with close monitoring. n
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