Biomarker test may drive treatment considerations for most common adult leukemia
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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.15,16,17,18 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.15,16,17,18,19 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:
It is not known if IMBRUVICA® is safe and effective in children.
Before taking IMBRUVICA®, tell your healthcare provider about all of your medical conditions, including if you:
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®?
What should I avoid while taking IMBRUVICA®?
What are the possible side effects of IMBRUVICA®?
IMBRUVICA® may cause serious side effects, including:
The most common side effects of IMBRUVICA® in adults with B-cell malignancies (MCL, CLL/SLL, WM and MZL) include:
The most common side effects of IMBRUVICA® in adults with cGVHD include:
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 click here to see the full Prescribing 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 June 2021.
3 National Cancer Institute SEER Program. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html. Accessed June 2021.
4 Leukemia & Lymphoma Society. Watch and wait. https://www.lls.org/leukemia/chronic-lymphocytic-leukemia/treatment/watch-and-wait. Accessed June 2021.
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 June 2021.
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 June 2021.
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 June 2021.
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 June 2021.
14 Imbruvica prescribing information. January 2020.
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 June 2021.
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 V4.2021. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed June 1, 2021. 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.