Biomarker test may drive treatment considerations for most common adult leukemia

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults.^[i],[ii] Approximately 20,160 Americans were diagnosed with CLL in 2022, with new cases at a rate of 4.7 per 100,000 in adult men and women.^[iii] Based on data from 2012-2018, the estimated five-year survival for diagnosed patients was about 87.9 percent.^[iii] Many newly diagnosed patients are put in “watch and wait,” where they are actively monitored for disease progression.^[iv]

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.^[v] Results from this simple test, known as cytogenic/fluorescence in situ hybridization or “FISH,” may help guide treatment decisions by providing key insights on the type of treatment needed.^[vi]

An examination from the informCLL^TM Prospective Observational Registry, one of the largest U.S.-based prospective registries of patients treated for CLL/SLL, revealed that only one-third of newly diagnosed patients in the registry (n=855) were tested for risk-associated mutations.^[vii] For patients who had relapsed or were refractory to current treatments (n=607), the rate of testing dropped to lower than one-fourth.^[vii] 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.^[vii]

In this study, nearly one-fourth of patients who underwent biomarker testing were shown to have CLL with del 17p.^[vii] 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.^[vii] Its presence frequently signals the loss or mutation of a key tumor-suppressive gene whose alteration is associated with a wide range of cancers.^[vii] CLL patients with this mutation may have more rapid disease progression than patients with normal cytogenetics.^[viii] 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 patients — some associated with a favorable prognosis and others, like the 17p deletion, with a poor one,” said Lindsey Roeker, MD, Hematology and Oncology, Memorial Sloan Kettering Cancer Center.^[ix] “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.^[x] 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.^[xi]

Lisa, who was diagnosed with CLL in 2018, found learning about genetic testing to be an integral part of her journey. “As a scientist with a Ph.D., I realized I needed to put in the work and learn as much as I could. I went online and started reading anything and everything from reliable sources. I also went to online support sites just to see what other people were saying. It’s important for patients to ask questions and learn their biomarkers so they can have informed conversations with their doctors about their treatment options.”

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.^[xii],[xiii] 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.^[xii],[xiii] Nonclinical studies show IMBRUVICA^® (ibrutinib) inhibits malignant B-cell proliferation and survival in vivo as well as cell migration and substrate adhesion in vitro.^[xiv]

IMBRUVICA^® 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.^[xiv] 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.^{[xv],[xvi],[xvii],[xviii]} 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 in combination with rituximab or obinutuzumab in the first line setting. It can also be administered as a single agent, or in combination with bendamustine and rituximab (BR) in the relapsed/refractory setting.

IMBRUVICA^® may cause serious side effects, including bleeding problems (hemorrhage), infections, heart rhythm problems (ventricular arrhythmias, atrial fibrillation, and atrial flutter), heart failure and death, high blood pressure (hypertension), decrease in blood cell counts, second primary cancers and tumor lysis syndrome (TLS). Common side effects include diarrhea, tiredness, muscle and bone pain, rash, and bruising. These are not all the possible side effects of IMBRUVICA^®. Please read the full Important Side Effect Information and full Important Product Information to learn about these and other risks.

Lisa found that working with a CLL specialist was important in determining the right treatment path for her. “A general oncologist will see many patients with many different types of cancer, but a CLL specialist is more likely to truly understand the nuances of this disease and the current treatments for it,” said Lisa. “I was able to understand my FISH test, but with the help of my CLL specialist, I was able to dive deeper and gain even more knowledge about the disease,” said Lisa.

After reviewing Lisa’s karyotypes, Lisa’s CLL specialist determined that she is a high-risk patient with mutations including deletion 17p. Based on this, her specialist recommended IMBRUVICA^® and she immediately began treatment through a clinical trial. Lisa discussed how IMBRUVICA^® works and any possible side effects with her doctor before she started treatment.

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 possibilities for HCPs treating this disease.

Historically, chemoimmunotherapy-based regimens have been the standard of care to treat patients with CLL. As of 2019, with approximately 200,000 people living with CLL in the U.S., 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.^[iii]

Uses

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 at about the same time each day.

IMBRUVICA® comes as 140mg and 70mg capsules, 560/420/280/140mg tablets, and a 70 mg/mL 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^® 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 (CLL/SLL) 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.

[i] National Cancer Institute. Dictionary of cancer terms. Definition of chronic lymphocytic leukemia. Accessed December 2022
[ii] American Cancer Society. What is chronic lymphocytic leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/what-is. Accessed December 2022.
[iii] National Cancer Institute SEER Program. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed December 2022.
[iv] Leukemia & Lymphoma Society. Watch and wait. https://www.lls.org/leukemia/chronic-lymphocytic-leukemia/treatment/watch-and-wait. Accessed December 2022.
[v] 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):114e2-124.e2. Accessed December 2022.
[vi] Wierda WG, Byrd JC, 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. Accessed December 2022.
[vii] Mato AR, Barrientos JC, 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 the 62^nd ASH Annual Meeting and Exposition. Accessed December 2022.
[viii] Döhner H, et al. N. Engl J Med. 2000;343(26):1910-1916. Accessed December 2022.
[ix] Puiggros A., Blanco G et al. (2014) Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go. BioMed research international, 2014, 435983. Accessed December 2022.
[x] Hallek M, Cheson B, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 2018;131:2745-2760. Accessed December 2022.
[xi] Gaidano G, Rossi D, et al. The mutational landscape of chronic lymphocytic leukemia and its impact on prognosis and treatment. Hematology Am Soc Hematol Edu Program 2017; 2017(1):329-337 DOI: https://DOI.org/10.1182/asheducation-2017.1.329. Accessed December 2022.
[xii] 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 December 2022.
[xiii] Brunner C, Muller B, et al. Bruton Tyrosine Kinase is involved in innate and adaptive immunity. Histol. Histopathol (2005) 20: 945-955. Accessed December 2022.
[xiv] IMBRUVICA^® (ibrutinib) prescribing information. https://www.imbruvica.com/files/prescribing-information.pdfhttps://www.imbruvica.com/files/prescribing-information.pdf.
[xv] 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. Accessed December 2022.
[xvi] RESONATE-2 8YR follow up manuscript: Barr et al. Blood Adv (2022) 6 (11): 3440–3450.
[xvii] Shanafelt T et al. Ibrutinib-Rituximab or Chemoimmunotherapy for CLL. The New England Journal of Medicine. August 1, 2019. https://www.nejm.org/DOI/full/10.1056/NEJMoa1817083. Accessed December 2022.
[xviii] Moreno C, Griel R, et al. Ibrutinib plus obinutuzumab in first-line treatment of CLL (iLLUMINATE): a multicentre, randomized, 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. Accessed December 2022.

PRC-09618 12/22