Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults.1,2 Each year, approximately 20,000 Americans are diagnosed with CLL, with new cases at a rate of 4.9 per 100,000 in adult men and women.3 The estimated five-year survival for diagnosed patients is about 87 percent.3 Many newly diagnosed patients are put in “watch and wait,” where they are actively monitored for disease progression.4
Patients with CLL present with varying degrees of severity and mortality risks. Fortunately, clinical assays exist to test diagnosed patients for specific biomarkers — genetic mutations — that serve as predictors of disease progression and mortality.5 Results from this simple test, known as cytogenetic/fluorescence in situ hybridization or “FISH,” may help guide treatment by providing key insights on the type of treatment needed.6
A recent examination from the informCLL™ Prospective Observational Registry, one of the largest US-based prospective registries of treated patients with CLL, revealed that only one-third of newly diagnosed patients in the registry (n=855) were tested for risk-associated mutations.7 For patients who had relapsed or were refractory to current treatments (n=607), the rate of testing dropped to lower than one-fourth.7 Data from this prospective analysis may indicate a “knowledge gap” in terms of prognostic marker testing and selection of therapies for patients with high-risk disease, including those with deletion 17p or TP53 mutations.7
In this study, nearly one-fourth of patients who underwent biomarker testing were shown to have CLL with del 17p.7 Predicting patient outcomes — including the likelihood of treatment failure and disease progression after treatment — could be clinically useful in determining an appropriate treatment course.
Among the various genetic markers associated with a CLL prognosis, del 17p is associated with a short watch-and-wait period, short median survival, and poor response to chemotherapy. Its presence frequently signals the loss or mutation of a key tumor-suppressive gene whose absence is associated with a wide range of cancers.6 CLL patients with this mutation may have more rapid disease progression than patients with normal cytogenics.8 With a tool at hand and the knowledge that this common mutation can quickly identify patients who may need aggressive treatment, the question remains, why is adoption of this tool, especially for patients who have relapsed, low?
“Chromosomal abnormalities in CLL are detected in up to 80 percent of patients9 – some associated with a favorable prognosis and others, like the 17p deletion, with a poor one,” said Lindsey Roeker, MD, Hematology and Medical Oncology, Memorial Sloan Kettering Cancer Center. “Each case of CLL is distinct; therefore, it is important for physicians to utilize these tests to determine genetic changes in the cancer cells that may influence the course of treatment. These biomarkers are important when counseling patients and treating this complex hematologic malignancy.”
Because predictive biomarkers may change over the course of the disease, genetic testing should be considered not only at diagnosis, but throughout the course of disease management as new mutations can develop over time or as a result of past treatments.10 In addition, with the vast number of available prognostic biomarkers, it has become difficult for physicians to determine which factors are most important for individual patients, and how to combine the results of multiple prognostic tests when some suggest an aggressive clinical course and others a more indolent one in the same patient.11
Role of Bruton’s tyrosine kinase (BTK)
In 1952, the pediatrician Ogden Bruton described a rare X-linked disease reflecting a near-complete loss of B cells and circulating antibodies.12,13 The science of the day was incapable of identifying the factor, the absence of which led to severe immunodeficiency. In 1993, when the tyrosine kinase now named in Bruton’s honor was cloned and characterized, physicians learned that Bruton’s tyrosine kinase (BTK) is a signaling molecule that activates B-cell receptor pathways which are essential to B-cell survival and proliferation.12,13 Nonclinical studies show that IMBRUVICA® inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.14
IMBRUVICA® (ibrutinib) was approved by the U.S. FDA for previously treated CLL in 2014, making it the first oral BTK inhibitor available for this patient population.14 IMBRUVICA® has since impacted the landscape for treating CLL, with five randomized Phase 3 clinical trials, and up to eight years of follow-up data which makes IMBRUVICA® the most extensively studied medicine in its class.15-18 IMBRUVICA® is indicated for the treatment of adult patients with CLL/small lymphocytic lymphoma (SLL) and CLL/SLL with deletion 17p. For CLL/SLL, IMBRUVICA® can be administered as a single agent, in combination with rituximab or obinutuzumab, or in combination with bendamustine and rituximab (BR) in both the first-line and relapsed/refractory setting.
The National Comprehensive Cancer Network® (NCCN®) recommends single-agent ibrutinib (IMBRUVICA®) as a preferred treatment option for patients with CLL/small lymphocytic lymphoma (SLL) with or without 17p deletion.19 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) reflect findings from a series of randomized Phase 3 clinical trials of ibrutinib (IMBRUVICA®) – including the Phase 3 RESONATE-2TM (n=133), E1912 (ECOG) (n=529), and iLLUMINATE (n=229) open-label trials — in CLL/SLL, alone or as part of a combination regimen with rituximab and obinutuzumab, respectively.15-19 Additionally, the NCCN Guidelines® provide guidance on multiple biomarkers associated with a favorable or unfavorable prognosis in CLL/SLL.19
IMBRUVICA® has played a key role in establishing the use of BTK inhibitors as a therapeutic agent for inhibiting B-cell development, maturation, survival and proliferation. Treatments are continuing to evolve and the introduction of agents like IMBRUVICA® has expanded the possibilities for HCPs treating this disease.
Historically, chemoimmunotherapy-based regimens have been the standard of care to treat patients with CLL. With 200,000 people living with CLL, there remains a significant need for more approved therapies and combinations as well as an increase in the utilization of genetic tests in newly diagnosed patients as testing for genetic mutations can help inform treatment decisions.3
What is IMBRUVICA® (ibrutinib)?
IMBRUVICA® (ibrutinib) is a prescription medicine used to treat adults with:
- Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
- Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
It is not known if IMBRUVICA® is safe and effective in children.
Important Side Effect Information
Before taking IMBRUVICA®, tell your healthcare provider about all of your medical conditions, including if you:
- have had recent surgery or plan to have surgery. Your healthcare provider may stop IMBRUVICA® for any planned medical, surgical, or dental procedure.
- have bleeding problems
- have or had heart rhythm problems, smoke, or have a medical condition that increases your risk of heart disease, such as high blood pressure, high cholesterol, or diabetes
- have an infection
- have liver problems
- are pregnant or plan to become pregnant. IMBRUVICA® can harm your unborn baby. If you are able to become pregnant, your healthcare provider will do a pregnancy test before starting treatment with IMBRUVICA®. Tell your healthcare provider if you are pregnant or think you may be pregnant during treatment with IMBRUVICA®.
- Females who are able to become pregnant should use effective birth control (contraception) during treatment with IMBRUVICA® and for 1 month after the last dose.
- Males with female partners who are able to become pregnant should use effective birth control, such as condoms, during treatment with IMBRUVICA® and for 1 month after the last dose.
- are breastfeeding or plan to breastfeed. Do not breastfeed during treatment with IMBRUVICA® and for 1 week after the last dose.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking IMBRUVICA® with certain other medicines may affect how IMBRUVICA® works and can cause side effects.
How should I take IMBRUVICA®?
- Take IMBRUVICA® exactly as your healthcare provider tells you to take it.
- Take IMBRUVICA® 1 time a day.
- Swallow IMBRUVICA® capsules or tablets whole with a glass of water.
- Do not open, break or chew IMBRUVICA® capsules.
- Do not cut, crush or chew IMBRUVICA® tablets.
- Take IMBRUVICA® at about the same time each day.
- If you miss a dose of IMBRUVICA® take it as soon as you remember on the same day. Take your next dose of IMBRUVICA® at your regular time on the next day. Do not take extra doses of IMBRUVICA® to make up for a missed dose.
- If you take too much IMBRUVICA® call your healthcare provider or go to the nearest hospital emergency room right away.
What should I avoid while taking IMBRUVICA®?
- You should not drink grapefruit juice, eat grapefruit, or eat Seville oranges (often used in marmalades) during treatment with IMBRUVICA®. These products may increase the amount of IMBRUVICA® in your blood.
What are the possible side effects of IMBRUVICA®?
IMBRUVICA® may cause serious side effects, including:
- Bleeding problems (hemorrhage) are common during treatment with IMBRUVICA®, and can also be serious and may lead to death. Your risk of bleeding may increase if you are also taking a blood thinner medicine. Tell your healthcare provider if you have any signs of bleeding, including: blood in your stools or black stools (looks like tar), pink or brown urine, unexpected bleeding, or bleeding that is severe or that you cannot control, vomit blood or vomit looks like coffee grounds, cough up blood or blood clots, increased bruising, dizziness, weakness, confusion, change in your speech, or a headache that lasts a long time or severe headache.
- Infections can happen during treatment with IMBRUVICA®. These infections can be serious and may lead to death. Tell your healthcare provider right away if you have fever, chills, weakness, confusion, or other signs or symptoms of an infection during treatment with IMBRUVICA®.
- Heart problems. Serious heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter), heart failure and death have happened in people treated with IMBRUVICA®, especially in people who have an infection, an increased risk for heart disease, or have had heart rhythm problems in the past. Your heart function will be checked before and during treatment with IMBRUVICA®. Tell your healthcare provider if you get any symptoms of heart problems, such as feeling as if your heart is beating fast and irregular, lightheadedness, dizziness, shortness of breath, swelling of the feet, ankles or legs, chest discomfort, or you faint. If you develop any of these symptoms, your healthcare provider may do tests to check your heart and may change your IMBRUVICA® dose
- High blood pressure (hypertension). New or worsening high blood pressure has happened in people treated with IMBRUVICA®. Your healthcare provider may start you on blood pressure medicine or change current medicines to treat your blood pressure.
- Decrease in blood cell counts. Decreased blood counts (white blood cells, platelets, and red blood cells) are common with IMBRUVICA®, but can also be severe. Your healthcare provider should do monthly blood tests to check your blood counts.
- Second primary cancers. New cancers have happened during treatment with IMBRUVICA®, including cancers of the skin or other organs.
- Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure and the need for dialysis treatment, abnormal heart rhythm, seizure, and sometimes death. Your healthcare provider may do blood tests to check you for TLS.
The most common side effects of IMBRUVICA® in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:
- muscle and bone pain
The most common side effects of IMBRUVICA® in adults with cGVHD include:
- mouth sores (stomatitis)
- muscle spasms
Diarrhea is a common side effect in people who take IMBRUVICA®. Drink plenty of fluids during treatment with IMBRUVICA® to help reduce your risk of losing too much fluid (dehydration) due to diarrhea. Tell your healthcare provider if you have diarrhea that does not go away.
These are not all the possible side effects of IMBRUVICA®. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of IMBRUVICA®
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use IMBRUVICA® for a condition for which it was not prescribed. Do not give IMBRUVICA® to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about IMBRUVICA® that is written for health professionals.
Please see the full Important Product Information.
To learn more about IMBRUVICA® visit www.IMBRUVICA.com.
1 National Cancer Institute. Dictionary of cancer terms. Definition of chronic lymphocytic leukemia. Accessed June 2021.
2 American Cancer Society. What is chronic lymphocytic leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is cll.html#:~:text=Chronic%20lymphocytic%20leukemia%20(CLL)%20is,then%20go%20into%20the%20blood. Accessed July 2022.
3 National Cancer Institute SEER Program. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed July 2022.
4 Leukemia & Lymphoma Society. Watch and wait. https://www.lls.org/leukemia/chronic-lymphocytic-leukemia/treatment/watch-and-wait. Accessed July 2022.
5 Mato A, Nabhan C, et al. Prognostic testing patterns and outcomes of chronic lymphocytic leukemia patients stratified by fluorescence in situ hybridization/cytogenetics: a real-world clinical experience in the Connect CLL Registry. Clinical Lymphoma, Myeloma & Leukemia. 2018;18(2):114.e2-124.e2. Accessed June 2021.
6 Wierda WG, Byrd JC, Abramson JS, Bilgrami SF, et al. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4. 2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18(2):185-217.
7 Mato AR, Barrientos JC, Sharman JP, et al. Real-world prognostic biomarker testing, treatment patterns and dosing among 1461 patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the informCLL prospective observational registry. Presentation at 62nd ASH Annual Meeting and Exposition. Accessed July 2022.
8 Döhner H, et al. N Engl J Med. 2000;343(26):1910-1916.
9 Puiggros, A., Blanco, G., & Espinet, B. (2014). Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go. BioMed research international, 2014, 435983.
10 Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745–2760.
11 Gaidano G., Rossi D.; The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Educ Program 2017; 2017 (1): 329–337. doi: https://doi.org/10.1182/asheducation-2017.1.329. Accessed July 2022.
12 Buggy J. and Elias L. Bruton Tyrosine Kinase (BTK) and Its Role in B-cell Malignancy. International Reviews of Immunology. 31:119–132, 2012 doi: 10.3109/08830185.2012.664797. Accessed July 2022.
13 Brunner C., Muller B., et al. Bruton’s Tyrosine Kinase is involved in innate and adaptive immunity. Histol Histopathol (2005) 20: 945-955. Accessed July 2022.
14 Imbruvica prescribing information.
15 Munir T., Brown JR., et al. Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019. Dec;94(12):1353-1363. doi: 10.1002/ajh.25638. Epub 2019 Oct 13. PMID: 31512258; PMCID: PMC6899718.
16 Burger J., Barr P., et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020 Mar;34(3):787-798. doi: 10.1038/s41375-019-0602-x. Epub 2019 Oct 18. PMID: 31628428; PMCID: PMC7214263.
17 Shanafelt, T., et al. Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. The New England Journal of Medicine. August 1, 2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1817073. Accessed July 2022.
18 Moreno C, Greil R, Demirkan F, et al., Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):43-56. doi: 10.1016/S1470-2045(18)30788-5. Epub 2018 Dec 3. Erratum in: Lancet Oncol. 2019 Jan;20(1):e10.
19 Referenced with permission from the NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V3.2022. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed July 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN® makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.