Examining CLL: Personal connection driving treatment research

Chronic lymphocytic leukemia (CLL) accounts for 38% of all leukemia diagnoses.¹ Due to CLL’s prominence, the treatment landscape is continuing to evolve with combination therapies and various chemotherapy-free treatment options.

To better understand CLL and the impact of Bruton’s tyrosine kinase (BTK) inhibitors on the treatment landscape — two leaders — James Dean, M.D., Ph.D. IMBRUVICA^® Global Development Lead and Executive Medical Director at Pharmacyclics LLC, an AbbVie company and Israel Arango-Hisijara, M.D., US Head, Lymphoid & Myeloid Malignancies, Medical Affairs at Janssen Oncology — discuss BTK inhibitors and data supporting treatment with IMBRUVICA^® (ibrutinib).

What is CLL? How common is it in the United States and who gets it?

Arango-Hisijara: Chronic lymphocytic leukemia, or CLL, is a type of slow-growing blood cancer that most commonly arises from white blood cells in the bone marrow, B cells.² It is the most common form of leukemia in the U.S., accounting for one-quarter of new cases and currently has no cure.^3,4

Something unique about CLL is that this disease often can be diagnosed incidentally, meaning that the patient initially has no symptoms.³ The disease is often discovered due to routine blood work or occasionally the patient will have mild symptoms, such as tiredness, fever, weight loss as well as swollen lymph nodes in the neck, under the arms, in the groin; they can sometimes also have pain in the upper left part of the abdomen, caused when the spleen increases in size.^1,3

Dean: In general, CLL is more commonly found in older people, with the average age of diagnosis around 70 years.⁴ Though rare, there are people who do get it at relatively young ages, 40 years of age or younger.⁴ Additionally, CLL is more commonly found in men than women.⁴

What inspired you to pursue your field of work? What is it about the blood cancer community that continues to drive you toward innovation?

Dean: Scientific exploration has always inspired me. In college, I was fortunate to have a mentor who suggested a combined M.D., Ph.D. degree program. Starting from my love of science, I then learned to love medicine and the care of patients.

Thinking back to when I made all these career path decisions and my more than 10 years in the pharmaceutical industry, it is motivating to see how the science is continuing to advance for cancer patients. In some shape or form, it’s most likely we all know of someone who has been touched by cancer. As we get older, more of our friends and family are directly impacted by cancer and other diseases. That’s kind of how life is, but at the same time, it’s a reminder of how important our research is and certainly a motivating factor to continue advancing the science.

 Arango-Hisijara: I feel the same way, James. I have a dear friend who was diagnosed with cancer and ultimately passed away. That makes a difference to me. My decision to move into oncology is due to my friend. This line of work provides the opportunity to bring treatment options to patients that may help in their disease journey as well as help healthcare providers make an informed decision for each patient.

The advent of BTK inhibitors, such as IMBRUVICA^®, have helped provide a potential treatment option for people with CLL. How do they work?

Arango-Hisijara: BTK inhibitors, like IMBRUVICA^®, work by blocking signals from a protein called Bruton’s tyrosine kinase that is found in B cells, this protein otherwise sends signals to B cells to stay alive and multiply.^2,5,6,7 With BTK inhibitors, the survival and multiplying of B cells stops with the potential to slow down the spread of CLL.^2,5,6,7

Dean: To go along with that, I like to describe the BTK signaling process as similar to a river. The abnormal cancer cell signaling is like storm waters flooding a river. A BTK inhibitor acts like a dam to catch that extra water and prevent the river from continuing to flow and flood. Likewise, this class of medicines helps to slow the cancer from growing by reducing this signaling.

What factors would make a patient a good candidate for first-line treatment with IMBRUVICA^®?

Dean: Every patient is unique. However, some factors to consider are age and genetic mutations. For example, CLL patients with deletion 17p — a genetic alteration associated with a short median survival and poor response to chemotherapy — have the option to take IMBRUVICA^®.^8,9

Arango-Hisijara: I agree with James. They all have their own comorbidities as well as treatment goals. There are several oral therapies available today which may be a preference to some patients as they can take the therapy at home. A patient’s treatment goals should be taken into consideration by their oncologist so they can tailor their first-line treatment.

Why is long-term data so important when studying CLL treatment?

Dean: The body of data available for IMBRUVICA^® including its long-term studies can help us understand the clinical benefits, and it also gives us a better understanding of its safety profile. It’s important for physicians to help communicate to patients on what to potentially expect in the short and long term as they are receiving their treatment, not only as it relates to effectiveness but also potential side effects that may occur.

Arango-Hisijara: Results from long-term studies can help better inform doctors and help patients better understand what to potentially expect during treatment when discussing options. IMBRUVICA^® long-term follow-up data as a monotherapy or as a combination may provide insight on potential progression-free survival and overall survival rates of certain patient groups.^10,11 

Could you speak to common side effects and potential serious adverse events (AEs) associated with IMBRUVICA^®? 

Dean: Similar to treatment outcomes, the body of data available for IMBRUVICA^® helps us understand its safety profile, including which adverse events (AEs) are most common early in treatment, and then most become less frequent over time.

IMBRUVICA^® may cause serious side effects including bleeding problems (hemorrhage), infections, heart rhythm problems (ventricular arrhythmias, atrial fibrillation and atrial flutter), heart failure, death, high blood pressure (hypertension), decrease in blood cell counts, secondary primary cancers, and tumor lysis syndrome (TLS). The most common adverse events overall in patients treated with IMBRUVICA^® are low platelet count, diarrhea, tiredness, muscle and bone pain, low white blood cell count, rash, low red blood cell count, bruising, and nausea.

With additional BTKi agents coming onto the market and having other Phase 3 data that’s newly available, certain AEs are being recognized in BTK inhibitors.¹² This offers the chance to further understand IMBRUVICA^® therapy, as physicians identify AEs that can be more proactively addressed.

Please see important safety information below.

What other considerations should patients and HCPs keep in mind when choosing a first-line treatment?

Dean: There are several first-line treatment options available for CLL. It’s important to consider each patient’s therapy goals and evaluate the benefits and risks. Physicians should also consider each patient’s medical conditions which might increase their risk for certain side effects. It’s also important to test and look for the presence of high-risk features such as gene mutations and chromosomal deletions as this will impact choices of National Comprehensive Cancer Network^® (NCCN^®)-recommended therapies.¹³

Arango-Hisijara: Those are all very important considerations. Patients should always communicate with their healthcare team any other concerns they have and what other medications they’re taking. This helps to avoid potential drug interactions as well as understand any other comorbidities, such as hypertension and heart disease, to properly manage treatment with IMBRUVICA^®.

Please see full prescribing information for complete dosage and administration details.

What resources are available for IMBRUVICA^® patients who are seeking additional support in navigating their medicine?

Arango-Hisijara: Patients prescribed IMBRUVICA^® can receive additional support through the By Your Side* program. The By Your Side program matches patients with an ambassador who can help patients by giving an overview of what to expect while on IMBRUVICA^®, including how to take their medication and possible side effects. By Your Side ambassadors can also connect patients with resources to explore savings options to help afford medication and understand insurance changes. By Your Side does not provide medical advice or work under the direction of the prescribing doctor, and patients should always talk to their doctor about any medical decisions and concerns they may have.

What are you most looking forward to in the future of understanding CLL?

Dean: The ultimate goal is to find a cure. Finding a cure for a disease that is slow growing, like CLL, may take many years. However, I look forward to continuing to focus on patient benefit, including researching ways to lengthen disease control as long as possible. To me, putting patients and their treatment outcomes first is critical to advancing the treatment landscape now.

Arango-Hisijara: I couldn’t agree more. Most of us who work in oncology know someone important in our lives affected by cancer. Our commitment to advancing the science is more than professional, it’s something driven by a deep personal connection. There is still new research that needs to be done to find options that continue to evolve treatment for patients, and we continue to explore a path toward a cure for this disease.

*IMBRUVICA^® By Your Side patient support program is not intended to provide medical advice, replace prescribed treatment plans, or provide treatment or case management services. Patients are advised to always talk to their healthcare provider and treatment team about any medical decisions and concerns they may have.

^†By Your Side Ambassadors are provided by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie Company, and do not provide medical advice or work under the direction of the prescribing healthcare professional (HCP). They are trained to direct patients to speak with their HCP about any treatment-related questions, including further referrals.

Uses

What is IMBRUVICA^® (ibrutinib)?

IMBRUVICA^® (ibrutinib) is a prescription medicine used to treat:

• Adults with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL).
• Adults with 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 at about the same time each day.

IMBRUVICA^® comes as capsules, tablets, and oral suspension.

• If your healthcare provider prescribes IMBRUVICA^® capsules or tablets:
  • 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.
• If your healthcare provider prescribes IMBRUVICA^® oral suspension:
  • See the detailed Instructions for Use that comes with IMBRUVICA^® oral suspension for information about the correct way to give a dose to your child. If you have questions about how to give IMBRUVICA^® oral suspension, talk to your healthcare provider.
  • Do not use if the carton seal is broken or missing.
  • 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^®
• 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:

• diarrhea
• tiredness
• muscle and bone pain
• rash
• bruising

The most common side effects of IMBRUVICA^® in adults or children 1 year of age and older with cGVHD include:

• tiredness
• low red blood cell count (anemia)
• bruising
• diarrhea
• low platelet count
• muscle and joint pain
• fever
• muscle spasms
• mouth sores (stomatitis)
• bleeding
• nausea
• stomach pain
• pneumonia
• headache

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.

References

1 Cancer.net. Leukemia – Chronic Lymphocytic – CLL: Statistics. https://www.cancer.net/cancer-types/leukemia-chronic-lymphocytic-cll/statistics. Last accessed May 2022.
2 Shaffer, A., Rosenwald, A. & Staudt, L. Lymphoid Malignancies: the dark side of B-cell differentiation. Nat Rev Immunol 2, 920–933 (2002). https://doi.org/10.1038/nri953. Last accessed May 2022.
3 Leukemia & Lymphoma Society. The CLL Guide Information for Patients and Caregivers. https://www.lls.org/sites/default/files/file_assets/cllguide.pdf. Last accessed May 2022.
4 Key Statistics for Chronic Lymphocytic Leukemia. (2021).https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html. Last accessed May 2022.
5 Genetics Home Reference. Isolated growth hormone deficiency. http://ghr.nlm.nih.gov/condition/isolated-growth-hormone-deficiency. Last accessed May 2022.
6 Turetsky A, et al. Single cell imaging of Bruton’s tyrosine kinase using an irreversible inhibitor. Scientific Reports. 2014;6:4782. Last accessed May 2022.
7 de Rooij MF, Kuil A, Geest CR, et al. The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood. 2012;119(11):2590-2594. Last accessed May 2022.
8 IMBRUVICA^® Prescribing Information. https://www.imbruvica.com/files/prescribing-information.pdf. Last accessed May 2022.
9 Mato A., Nabhan C., et al. Prognostic Testing Patterns and Outcomes of Chronic Lymphocytic Leukemia Patients Stratified by Fluorescence In Situ Hybridization/Cytogenics: A Real-World Clinical Experience in the Connect CLL Registry. Clinical Lymphoma, Myeloma & Leukemia. 2018;18(2):114.e2-124.e2 Last accessed May 2022.
10 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. Last accessed May 2022.
11 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. Last accessed May 2022.
12 Ahn IE, Brown JR. Targeting Bruton’s tyrosine kinase in Cll. Frontiers in Immunology. 2021;12. doi:10.3389/fimmu.2021.687458. Last accessed May 2022.
13 Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V2.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Last accessed May 4, 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.

PRC-09615 09/22