The evolution of chronic lymphocytic leukemia: important advances over 50 years
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The first fossil records of cancer date back more than thousands of years.1 However, the first clinical diagnosis of blood cancer wasn’t until 1832 by British pathologist, Dr. Thomas Hodgkin.2
The past 50 years have been groundbreaking for treating blood cancers, particularly chronic lymphocytic leukemia (CLL), the most common leukemia in adults.2,3 Until recently, there were limited treatment options for CLL beyond chemotherapy regimens.
Decades of hard work and research have given scientists a far better understanding of the disease today, including its pathophysiology and genetic mutations. This research has paved the way for pivotal innovations, marking a new era for people diagnosed with CLL and physicians who specialize in the treatment of this form of blood cancer.
Take a look back at six significant highlights:
1970: Recognizing leukemia cells
In the early 1970s, it became possible to recognize B and T cells in the blood, which was a critical step towards identifying CLL.4
1975: Setting the stage
Until the mid-1970s, CLL had been known for being unpredictable in its disease course, making it difficult to anticipate patient outcomes.5 In 1975, the first commonly used staging system in the U.S. was established by Dr. Kanti Rai.6 The Rai Staging System estimates the survival of patients with CLL at the time of diagnosis or during the course of disease.6,7 This system divides CLL into five stages based on symptom presentation, laboratory results, and physical assessments.6
Shortly after the Rai Staging System was established, Dr. Jacques-Louis Binet developed the three-stage Binet Staging System, which classifies patients as low- to high-risk.5,7 The Binet classification system is commonly used across Europe.5,8 Both systems are based on physical aspects like lymphadenopathy, splenomegaly, and hepatomegaly as well as extent of anemia and thrombocytopenia in the peripheral blood.7
Today, the Rai and Binet Staging Systems remain the gold standards for staging CLL and help determine patient prognosis, including plan for treatment.8
2000: Putting genetics on the map
Genetic testing wasn’t commonly used until the early 2000s.9,10 Genetic mutations can be an indicator of the likelihood of disease progression and treatment response in patients.11 These are determined by various tests, including FISH testing, which looks for changes in chromosomes and genes, as well as DNA sequencing to identify IGHV mutation status and TP53 mutation.12
Today, up to 80 percent of patients with CLL have a genetic abnormality that may help inform a treatment plan.13
2009-2010: Introduction of chemoimmunotherapy regimens
In the early 2000s, the first immunotherapy regimens were approved in combination with chemotherapy by the U.S. Food and Drug Administration (FDA).14,15
2014: In with the new
In 2014, several treatment options were approved by the FDA in CLL, offering therapeutic alternatives to chemotherapy regimens for the first time.16-20 These additional therapies included IMBRUVICA® (ibrutinib), an oral medicine that blocks the Bruton’s tyrosine kinase (BTK). By blocking BTK, IMBRUVICA® may help move abnormal B cells out of their nourishing environments in the lymph nodes, bone marrow, and other organs.21,22
Since this time, additional therapies have been approved by the FDA for the treatment of CLL, expanding the arsenal of therapies available that work on different pathways.23,24
As of early 2019, the National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 28 leading cancer centers devoted to patient care, research, and education, recommends ibrutinib (IMBRUVICA®) as a preferred regimen for the initial treatment of CLL/SLL and is the only Category 1 single-agent regimen for patients without deletion 17p.8
Today: The future looks bright
Treatment continues to evolve, particularly as researchers investigate new medicines with complementary mechanisms of action for new therapeutic approaches using combination regimens.25 In addition, researchers are beginning to evaluate chimeric antigen receptor (CAR) T-cell therapy in CLL.26
The scientific community continues to work hard to better understand this complex blood cancer and improve treatment approaches for patients diagnosed with CLL.
Learn more about IMBRUVICA® at www.IMBRUVICA.com.
IMBRUVICA® Important Safety Information
WARNINGS AND PRECAUTIONS
Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in 3% of patients, with fatalities occurring in 0.3% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Bleeding events of any grade, including bruising and petechiae, occurred in 44% of patients treated with IMBRUVICA®.
The mechanism for the bleeding events is not well understood.
IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding.
Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.
Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 24% of 1,124 patients exposed to IMBRUVICA® in clinical trials. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections.
Monitor and evaluate patients for fever and infections and treat appropriately.
Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (23%), thrombocytopenia (8%), and anemia (3%) based on laboratory measurements occurred in patients with B‑cell malignancies treated with single agent IMBRUVICA®.
Monitor complete blood counts monthly.
Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0.2% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 4% of 1,124 patients exposed to IMBRUVICA® in clinical trials. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias.
Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines.
Hypertension: Hypertension of any grade occurred in 12% of 1,124 patients treated with IMBRUVICA® in clinical trials. Grade 3 or greater hypertension occurred in 5% of patients with a median time to onset of 5.9 months (range, 0.03 to 24 months).
Monitor blood pressure in patients treated with IMBRUVICA® and initiate or adjust anti-hypertensive medication throughout treatment with IMBRUVICA® as appropriate.
Second Primary Malignancies: Other malignancies (10%) including non-skin carcinomas (4%) have occurred in 1,124 patients treated with IMBRUVICA® in clinical trials. The most frequent second primary malignancy was non-melanoma skin cancer (6%).
Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions.
Monitor patients closely and treat as appropriate.
Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA® and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.
B-cell malignancies: The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (58%)*, diarrhea (41%), anemia (38%)*, neutropenia (35%)*, musculoskeletal pain (32%), rash (32%), bruising (31%), nausea (26%), fatigue (26%), hemorrhage (24%), and pyrexia (20%).
The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (18%)*, thrombocytopenia (16%)*, and pneumonia (14%).
Approximately 7% (CLL/SLL), 14% (MCL), 14% (WM) and 10% (MZL) of patients had a dose reduction due to adverse reactions. Approximately 4-10% (CLL/SLL), 9% (MCL), and 7% (WM [5%] and MZL [13%]) of patients discontinued due to adverse reactions.
cGVHD: The most common adverse reactions (≥20%) in patients with cGVHD were fatigue (57%), bruising (40%), diarrhea (36%), thrombocytopenia (33%)*, muscle spasms (29%), stomatitis (29%), nausea (26%), hemorrhage (26%), anemia (24%)*, and pneumonia (21%).
The most common Grade 3 or higher adverse reactions (≥5%) reported in patients with cGVHD were pneumonia (14%), fatigue (12%), diarrhea (10%), neutropenia (10%)*, sepsis (10%), hypokalemia (7%), headache (5%), musculoskeletal pain (5%), and pyrexia (5%).
Twenty-four percent of patients receiving IMBRUVICA® in the cGVHD trial discontinued treatment due to adverse reactions. Adverse reactions leading to dose reduction occurred in 26% of patients.
*Treatment-emergent decreases (all grades) were based on laboratory measurements.
CYP3A Inhibitors: Modify IMBRUVICA® dose as described in USPI sections 2.4 and 7.1.
CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.
Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA® dose.
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1Stone, MJ. Baylor University Medical Center Proceedings. Thomas Hodgkin: medical immortal and uncompromising idealist. October 2005. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1255947/. Accessed May 2019.
2Egle, A. Magazine of European Medical Oncology. Milestones in Chronic Lymphocytic Leukemia. February 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357250/pdf/12254_2017_Article_318.pdf. Accessed May 2019.
3Leukemia & Lymphoma Society. Chronic Lymphocytic Leukemia. https://www.lls.org/sites/default/files/file_assets/PS34_CLL_Booklet_2017_9_7FINAL.pdf. Access May 2019.
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5Binet, J, Leporrier, M, Dighiero G, et al. A clinical staging system for chronic lymphocytic leukemia. Cancer. August 1977. https://onlinelibrary.wiley.com/doi/epdf/10.1002/1097-0142%28197708%2940%3A2%3C855%3A%3AAID-CNCR2820400239%3E3.0.CO%3B2-1. Accessed May 2019.
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7CLL Global Research Foundation. Chronic Lymphocytic Leukemia; Prognostic Factors. http://cllglobal.org/cll-information/prognostic-factors/. Accessed May 2019.
8Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma V5.2019. © National Comprehensive Cancer Network, Inc. 2019. All rights reserved. Accessed May, 24, 2019. 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.
9Dohner, H, Stilgenbauer, S, Benner, A, et al. Genomic aberrations and survival in chronic lymphocytic Leukemia. The New England Journal of Medicine. December 2000. https://www.nejm.org/doi/10.1056/NEJM200012283432602?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.nih.gov. Accessed May 2019.
10Chiorazzi, N, Rai, K, Ferrarini, M. Chronic Lymphocytic Leukemia. The New England Journal of Medicine. February 2005; 352:804-815. https://www.nejm.org/doi/full/10.1056/NEJMra041720. Accessed May 2019.
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13Moreno, C. and Montserrat E. Genetic lesions in chronic lymphocytic leukemia: what’s ready for prime time use? Haematologica. January 2010. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805746/pdf/0950012.pdf. Accessed May 2019.
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17Angelo de Claro, R, McGinn, K, Verdun, et al. FDA Approval: Ibrutinib for Patients with Previously Treated Mantle Cell Lymphoma and Previously Treated Chronic Lymphocytic Leukemia. Clinical Cancer Research. August 2015. http://clincancerres.aacrjournals.org/content/21/16/3586. Accessed May 2019.
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25Ujjani C, Wang H, Skarbnik A, et al. A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL. Blood Advances. April 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894261/pdf/advances015263.pdf. Accessed May 2019.
26Fraietta J, Lacey S, Orlando E, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. May 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117613/pdf/nihms-981956.pdf. Accessed May 2019.