How Unmutated IGHV Affects Treatment “In people with unmutated IGHV, healthcare professionals tend not to recommend traditional chemoimmunotherapy because it tends to produce shorter remissions and a higher risk of the disease returning,” says Khan. Instead, treatment typically involves targeted therapies, such as BTK inhibitors or combination treatments with venetoclax.e60dc2a1-f33c-4a05-9b50-8e3e8e5976292eb98b9d-f7fb-4b8c-a7a7-83ec4704f831 Khan notes that a cancer care team may also consider a combination of acalabrutinib and venetoclax for some people with this biomarker.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293d82d4d7-87ac-4378-b1fc-90295d41ec4a
Resources We Trust Cleveland Clinic: BTK InhibitorsMayo Clinic: Chronic Lymphocytic Leukemia: How Does Genetic Testing Impact My Treatment Options?CLL Society: Test Before Treat HandoutLeukemia Research Foundation: Leukemia Biomarker TestingMedlinePlus: TP53 Gene
Before your care team recommends a chronic lymphocytic leukemia (CLL) treatment plan, they’ll likely request genetic testing.e60dc2a1-f33c-4a05-9b50-8e3e8e597629bb314ccd-be58-49a3-b07a-a84ea6041758 Despite the name, these tests aren’t looking for genes that you inherited or share with family members. Instead, they’re looking at DNA changes in the leukemia cells that make your type of CLL unique to you.e60dc2a1-f33c-4a05-9b50-8e3e8e597629c441cc27-9516-4485-b0f0-115f35bf1dc8 “These genetic changes, known as biomarkers, are like fingerprints that can provide important information about the cancer and how to best treat it,” says Krushangi Patel, MD, a medical oncologist and assistant clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope Orange County, based in Irvine, California. Understanding the CLL biomarkers that oncologists often test for and what the results can mean for your care can help you take an active role in decisions about your treatment . This article helps break down these changes and explain what they may mean for you.
What Mutated and Unmutated IGHV Mean In general, CLL with a mutated IGHV gene means the original B cell completed more of its normal maturation process before becoming cancerous, says Kerry Rogers, MD , a hematology-oncologist at The Ohio State University Comprehensive Cancer Center in Columbus. Contrary to what you might expect, “mutated” in this context is associated with a favorable outlook, as leukemia with a mutated IGHV tends to grow more slowly.e60dc2a1-f33c-4a05-9b50-8e3e8e59762976c7ba35-9823-4c2e-9903-0f2474266593 “CLL with unmutated IGHV is usually a little faster-growing and more aggressive, as it is a less mature cancer,” says Dr. Rogers.
How Mutated IGHV Affects Treatment Several treatments are available for people with mutated IGHV and no high-risk biomarkers, such as the ones discussed below.e60dc2a1-f33c-4a05-9b50-8e3e8e597629fd4d2b50-5c52-4578-9c60-70bda542bb7f “Chemoimmunotherapy, such as fludarabine, cyclophosphamide, and rituximab (FCR), is one option for younger, otherwise healthy people in this group, as it can lead to a long, treatment-free remission,” Dr. Koprivnikar says. Targeted therapies, particularly Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib (Imbruvica) and acalabrutinib (Calquence), are also effective options for those in this group who prefer to avoid chemotherapy -related side effects.e60dc2a1-f33c-4a05-9b50-8e3e8e597629f73e6770-0fa9-403d-9b58-7d5d48222ac4 You’d take these oral medications indefinitely as long as they’re working well and not causing intolerable side effects. This is known as continuous treatment.e60dc2a1-f33c-4a05-9b50-8e3e8e5976296ac84263-831b-40f9-aacb-eca846c5a3b0 Another alternative is fixed-duration treatment. Unlike continuous treatment, a doctor administers fixed-duration therapy for a set period.e60dc2a1-f33c-4a05-9b50-8e3e8e597629188ba4a3-6227-46e4-98da-ec699a99928d Fixed-term treatment generally includes regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (Venclexta). Rogers says that many people with mutated IGHV who receive fixed-duration treatment remain in remission for years after treatment ends without needing to take any medication afterward. Your oncology team can help you determine if this is an option for you.
Why Is Biomarker Testing Important? The combination of these results helps your oncologist understand what type of CLL you have, how quickly it might progress, and which treatments are most likely to work.e60dc2a1-f33c-4a05-9b50-8e3e8e597629516b3894-1c94-49e9-9a30-570cdbdd883e “For example, CLL with mutated IGHV, normal chromosomes, and an unmutated TP53 gene is likely to behave differently from CLL with unmutated IGHV, 17p deletion, and a mutated TP53,” says Adeel Khan, MD , a hematology-oncologist and epidemiologist at the University of Texas Southwestern Medical Center in Dallas. This means two people can share the same CLL diagnosis and yet have cancers that act very differently and require very different treatments. Dr. Khan says that your care team will typically perform biomarker testing at diagnosis and repeat these tests before starting treatment or if the CLL comes back after treatment. “That’s because the genetic makeup of CLL cells can change over time, so earlier results may not accurately reflect how those cells are behaving today, especially when it’s time to choose a treatment,” he says.
How del(17p) Affects Treatment In the past, people with del(17p) had a relatively poor outlook and did not respond well to traditional chemotherapy. “This is because chemotherapy relies on the TP53 gene — the very gene that’s missing in del(17p) — to signal to cancer cells that they need to die,” Koprivnikar says. Without that gene, chemotherapy becomes less effective at killing cancer cells while still causing side effects. But that has changed significantly. “[Detection of del(17p)] often helps steer us away from chemotherapy and toward therapies that are more likely to benefit the patient,” Patel says. The modern standard of care for CLL with del(17p) is to use novel targeted agents that act through pathways independent of TP53.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e00f8d4b-3a3d-4443-ae54-84cea991a8aa The main options are continuous BTK inhibitors or a fixed-duration venetoclax-based treatment, says Patel. Both can be effective, and the best choice depends on several factors, including your overall health, how long you’d prefer to be on treatment, and which side effects you’re most comfortable managing.e60dc2a1-f33c-4a05-9b50-8e3e8e59762933c69451-f2e2-448a-9268-60fa0cb550cc
IGHV Mutation IGHV Mutational Status IGHV is a gene present in B cells, the type of white blood cell involved in CLL.e60dc2a1-f33c-4a05-9b50-8e3e8e5976292dfd2c46-85db-4d82-ae17-dfbac0d4aa0f As they mature, healthy B cells normally go through a refinement process to help them better recognize and respond to germs, says Khan. In doing so, a permanent fingerprint develops in their IGHV gene. “When a B cell has undergone this process, it is said to have a mutated IGHV gene. When it has not, meaning the cell was arrested in development before completing this maturation step, it is called unmutated,” says Khan. The leukemia cells in CLL may carry either a mutated or unmutated version of the IGHV gene, and that’s what the IGHV mutation test is looking for.e60dc2a1-f33c-4a05-9b50-8e3e8e597629da2a1c1c-82d2-4959-ad14-be43d4254113 IGHV mutational status is one of several factors that help guide treatment decisions for CLL.
17p Deletion 17p Deletion or del(17p) Another important biomarker your oncologist will look for is 17p deletion, often written as del(17p).e60dc2a1-f33c-4a05-9b50-8e3e8e597629b3bc1bf0-18ed-49ed-a9e8-3ca749c82eaa This biomarker is identified by FISH.e60dc2a1-f33c-4a05-9b50-8e3e8e59762968b66fb3-e1e9-4614-83dd-1ee71f03341a In a FISH test, a healthcare professional uses special fluorescent dyes that attach to small parts of certain chromosomes but not others. This allows them to see the DNA and chromosomes in the cell without needing to grow their own cells, unlike other tests, such as in cytogenetics, which often means you get your results sooner.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293be9bf4d-c830-4e40-a91e-b35193a919ea “If your results show del(17p) is present, it means a small but vital piece of chromosome 17 is missing [deleted] from your leukemia cells,” Dr. Patel says. Losing that part of the chromosome also removes a vital gene called TP53.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293d2b9393-d0ad-4ebe-a36b-bbd43c7a7bda TP53 acts as a quality-control system for cells. Its job is to detect damaged DNA and tell the cell to either repair it or self-destruct — an important safeguard that prevents abnormal cells from multiplying uncontrollably.e60dc2a1-f33c-4a05-9b50-8e3e8e597629e17a08c7-c7b8-4c54-abe8-f8747d9e7846 Without that protection, leukemia cells can survive longer, grow more aggressively, and become harder to control, says Patel. As a result, del(17p) is a high-risk feature, and people with this deletion often need to start treatment sooner than those without, Rogers says.
CLL Biomarkers What Are CLL Genetic Biomarkers? Your DNA serves as the instruction manual for your body’s cells. In CLL, some of the instructions inside the leukemia cells may be missing, altered, or copied incorrectly.e60dc2a1-f33c-4a05-9b50-8e3e8e59762945a065e1-2f7c-4c4b-a133-e5192ebde945 Doctors call these errors genetic biomarkers. These biomarkers can cause the cells to multiply uncontrollably and survive longer than they should, says Jamie Koprivnikar, MD , a board-certified hematology-oncologist at the John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, New Jersey. The main CLL biomarker tests your care team may order include the following:e60dc2a1-f33c-4a05-9b50-8e3e8e59762999ab8a29-ff09-4c3a-b031-510a51227649 Immunoglobulin heavy chain variable (IGHV) mutation testing Fluorescence in situ hybridization (FISH), which looks for anomalies in chromosomes (structures that carry your DNA), including 17p deletion Tumor protein 53 (TP53) test, which checks for mutation in the TP53 gene A healthcare professional will often take a blood sample for these tests, though they may sometimes use a bone marrow sample.e60dc2a1-f33c-4a05-9b50-8e3e8e5976299c7b1750-e02b-4dbe-b5ed-46ad59ec99fa
TP53 Mutation TP53 Mutation Unlike del(17p), where the TP53 gene is missing altogether, a TP53 mutation means the gene is present but contains an error in its code and can’t do its job.e60dc2a1-f33c-4a05-9b50-8e3e8e597629026eeec8-da33-428f-bcdb-c894090475cd Your results may show TP53 as either mutated or unmutated. Here, “mutated” is not a favorable result (unlike IGHV, where the mutated gene is associated with a better outcome).e60dc2a1-f33c-4a05-9b50-8e3e8e59762946f6ee33-34ac-4973-a1ad-a821d0038a1f “A TP53 mutation is considered a high-risk feature because the cells’ quality-control system is disabled, which can lead to a more aggressive form of CLL,” says Koprivnikar. An unmutated TP53 gene, sometimes called “wild-type” TP53, means the gene is present and functioning normally.e60dc2a1-f33c-4a05-9b50-8e3e8e597629a789a416-b48d-4cf4-a2ed-a97a04d9f7c4
How TP53 Mutation Affects Treatment “Chemoimmunotherapy regimens, including FCR, bendamustine-rituximab, and chlorambucil-based combinations, are not recommended if you have a TP53 mutation,” says Khan. These treatments are unlikely to work well and may expose you to unnecessary side effects of chemotherapy.e60dc2a1-f33c-4a05-9b50-8e3e8e5976293ffb9e9f-cd33-4c95-8282-9996ee9c4531 As with del(17p), Khan says that the recommended treatment for TP53 mutation is novel targeted therapies, such as continuous BTK inhibitor therapy or fixed-duration venetoclax-based combination regimens. “Your oncologist may consider combining a BTK inhibitor with venetoclax,” he says.e60dc2a1-f33c-4a05-9b50-8e3e8e5976291443a138-8c96-4fbd-a5fc-41b53b77bffc Although TP53 mutations can make CLL more challenging to treat, more treatment options are available today than ever before.e60dc2a1-f33c-4a05-9b50-8e3e8e5976299a4764d7-cdc7-4fac-a9e4-a5b53ce2003c Choosing among them often comes down to factors such as your overall health and what matters most to you in terms of treatment duration and side effects.e60dc2a1-f33c-4a05-9b50-8e3e8e5976294c073c9b-ce19-4f1f-92d7-d40ff251fd3c Discuss your biomarker results with your oncology team to help you find the safest, most effective, and least disruptive treatment for you.
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