Research in chronic lymphocytic leukemia (CLL)
We are always learning more about cancer. Researchers and healthcare professionals use what they learn from research studies to develop better practices that will help prevent, find and treat chronic lymphocytic leukemia (CLL). They are also looking for ways to improve the quality of life of people with CLL.
The following is a selection of research showing promise for CLL. We’ve included information from PubMed, which is the research publication database of the National Library of Medicine. Each research article in PubMed has an identity number (called a PMID) that links to a brief overview (called an abstract). We have also included links to abstracts of the research presented at meetings of the American Society of Clinical Oncology (ASCO), which are held throughout the year. You can find information about ongoing clinical trials in Canada from CanadianCancerTrials.ca and ClinicalTrials.gov. Clinical trials are given an identifier called a national clinical trial (NCT) number. The NCT number links to information about the clinical trial.
Researchers are trying to find better ways to help doctors predict a prognosis (how likely it is that the cancer can be successfully treated or that it will come back after treatment) for CLL. They are also trying to determine the best treatment options based on certain characteristics of the disease, such as specific biomarkers. Biomarkers are substances, such as proteins, genes or pieces of genetic material like DNA and RNA, that are found naturally in the body. They can be measured in body fluids, including blood, lymph fluid and bone marrow, or on certain types of cells, such as cancer cells. Doctors can look for and measure these biomarkers to check if cancer is present or that it is responding to treatment.
Prognostic and predictive biomarkers for CLL can be used to help plan treatment. Prognostic biomarkers can be used to identify people who have a greater risk that the disease will progress or come back after treatment (recur or relapse). Predictive biomarkers are used to identify people who are more likely to have a favourable or unfavourable effect from treatment compared to people without the biomarker. Researchers are looking at the following biomarkers to see if they can help doctors diagnose, predict a prognosis for and find out which treatments will benefit a person with CLL:
- NOTCH1 (Leukemia, PMID 27773930)
- SF3B1 (Blood, PMID 26837699)
- CXCR4 (Haematologica, PMID 26589908; Leukemia, PMID 26582643)
- BTK (Journal of Clinical Oncology, PMID 28418267; Blood, PMID 28049639)
- PLCG2 (Blood, PMID 28049639)
- interleukin and CD20 (Haematologica, PMID 28126961)
- TP53 (Leukemia, PMID 27909343; Lancet Oncology, PMID 27637985)
- KRAS (Blood, PMID 27226433)
- ATM (Blood, PMID 26837699; ASCO, Abstract 7523)
- BIRC3 (Blood, PMID 26837699)
- POT1 (Blood, PMID 27226433)
- XPO1 (American Journal of Hematology, PMID 27468087)
- B2M (ASCO, Abstract 7521; ClinicalTrials.gov, NCT01578707)
The International Prognostic Index for CLL is a model that researchers recently developed to help doctors determine the outcome for the disease. It looks at several prognostic biomarkers for CLL together to better identify people who have a low, intermediate or high risk that their disease will progress or relapse (Lancet Oncology,PMID 27185642).
Find out more about research in prognosis.
Researchers are looking for new ways to improve treatment for CLL. Advances in cancer treatment and new ways to manage the side effects from treatment have improved the outlook and quality of life for many people with cancer. The following is noteworthy research into treatment for CLL.
Chemotherapy and targeted therapy
First-line treatments for CLL usually involve chemotherapy combined with a monoclonal antibody that targets CLL cells. Although these regimens work well and can bring about a remission that lasts several years, they are not considered cures. As a result, researchers continue to look for targeted therapy drugs that are more effective in treating CLL and cause fewer side effects. They are designing these targeted therapy drugs based on a better understanding of leukemia cells. Targeted therapies are generally designed to block key pathways that leukemia cells need to survive and grow. In addition to studying how new targeted therapies work on their own, researchers are also looking at using either 2 or more new targeted therapies together or targeted therapies in combination with chemotherapy regimens.
Researchers are studying the following chemotherapy drugs in treating CLL:
- lenalidomide (Revlimid) (Biology of Blood and Marrow Transplantation, PMID 28495642; Cancer Immunology, Immunotherapy, PMID 27815572)
- bortezomib (Velcade) (Leukemia and Lymphoma, PMID 28103725)
- romidepsin (Istodax) (Leukemia and Lymphoma, PMID 28103725)
Monoclonal antibodies that researchers are studying to treat CLL include:
- otlertuzumab (British Journal of Haematology, PMID 27977057)
- bevacizumab (Avastin) (Oncotarget, PMID 27861157)
- ublituximab (British Journal of Haematology, PMID 28220479, PMID 27982425)
New drug combinations that researchers are studying in clinical trials include:
- lenalidomide and rituximab (Rituxan) (Leukemia Research, PMID 27285853)
- fludarabine (Fludara), cyclophosphamide (Procytox) and lenalidomide (Leukemia and Lymphoma, PMID 27881039)
- ofatumumab (Arzerra), fludarabine and cyclophosphamide (Leukemia and Lymphoma, PMID 27731748)
- fludarabine, bendamustine (Treanda) and rituximab (Oncotarget, PMID 27655665)
- bendamustine and rituximab (British Journal of Haematology, PMID 27377970)
- idelalisib (Zydelig), bendamustine and rituximab (Lancet Oncology, PMID 28139405)
- mitoxantrone and low-dose rituximab (Leukemia, PMID 28336937)
- obinutuzumab (Gazyva) and ibrutinib (Imbruvica) (Cancer Journal, PMID 26841018)
- idelalisib and ofatumumab (Lancet Haematology, PMID 28257752)
- venetoclax and rituximab (Lancet Oncology, PMID 28089635)
- ofatumumab consolidation treatment (Lancet Haematology, PMID 27570087)
Cyclin-dependent kinase (CDK) inhibitors
CDKs are proteins that control the cell cycle. CDK inhibitors block these proteins to help slow or stop the growth of cancer cells. The following CDK inhibitors are showing promise for CLL that has come back after treatment (relapsed) or that doesn’t respond to treatment (refractory):
- flavopiridol (Alvocidib) (Annals of Hematology, PMID 27118540)
- dinaciclib (Blood, PMID 28126927)
- AT7519M (Leukemia and Lymphoma, PMID 27750483)
PI3K (phosphoinositide 3-kinase) inhibitors
PI3K inhibitors work by switching off PI3K, which is an enzyme in cells that makes them grow and divide. Idelalisib is a PI3K inhibitor used to treat CLL. Researchers are looking at the following PI3K inhibitors for treating CLL:
- duvelisib (Leukemia, PMID 28017967; Expert Opinion on Investigational Drugs, PMID 28388280; ASCO, Abstract 7533)
- umbralisib (ASCO, Abstract 7530; ClinicalTrials.gov, NCT02742090)
AKT inhibitors work by switching off AKT, a group of enzymes involved in cell growth and survival. Researchers are studying MK-2206, an AKT inhibitor, combined with chemoimmunotherapy to treat CLL (American Journal of Hematology, PMID 28402581).
Bruton’s tyrosine kinase (BTK) inhibitors
BTK inhibitors, such as ibrutinib, are very effective in treating relapsed and refractory CLL and previously untreated CLL. It is also particularly effective in treating CLL that has a very high risk of progressing or relapsing, including CLL in people with TP53 gene mutations. Other BTK inhibitors showing promise for treating CLL in early research studies include:
- acalabrutinib (New England Journal of Medicine, PMID 26641137; Blood, PMID 26542378; Lancet Oncology, PMID 26655421)
- CC-292 (Haematologica, PMID 27151992)
- ONO/GS-4059 (Blood, PMID 26542378)
- zanubrutinib (ASCO, Abstract TPS7581)
mTOR inhibitors slow or stop cancer growth by blocking mTOR, which is a protein that regulates cellular metabolism and growth and how quickly cells multiply. This protein can trigger cancer cells to grow and new blood vessels to form, which cancers need to grow. Researchers are looking at the following mTOR inhibitors for treating CLL:
- everolimus (Afinitor) (Leukemia and Lymphoma, PMID 26699397)
- voxtalisib (XL765, SAR245409) (British Journal of Haematology, PMID 27293194)
Immunotherapy boosts or helps the immune system find and destroy cancer cells. Researchers are studying the following types of immunotherapy for CLL.
Immune checkpoint inhibitors
Immune checkpoint inhibitors work by stopping cancer cells from affecting immune system cells in our bodies. The immune system normally stops itself from attacking healthy cells in the body by having some cells make specific proteins called checkpoints. Cancer cells sometimes use these checkpoints to avoid being attacked by the immune system. Immune checkpoint inhibitors are monoclonal antibodies that work by blocking checkpoint proteins so T cells (a type of white blood cell) can attack and kill cancers cells. Researchers are studying the immune checkpoint inhibitor pembrolizumab (Keytruda) to treat CLL (Blood, PMID 28424162).
Engineered chimeric antigen receptor (CAR) T cells
T cells are part of the immune system. They help fight infection and destroy abnormal cells, including cancer cells. Doctors take T cells from a person’s blood and genetically engineer, or modify, them in the lab so they have chimeric antigen receptors (CARs) on their surface. CARs are proteins that make the T cells recognize cancer cells. Doctors can grow CAR T cells in the lab until they have billions of them. They then infuse the CAR T cells back into the person’s body, where they will multiply, and then target and kill cancer cells. Researchers are studying CAR T cells directed against CD19 as a treatment for CLL (Immunotherapy, PMID 29421980; Leukemia and Lymphoma, PMID 29043880; Current Treatment Options in Oncology, PMID 27098534; Journal of Clinical Oncology, PMID 28715249).
Find out more about research in immunotherapy.
Stem cell transplant
Stem cell transplant replaces a person’s blood-forming (hematopoietic) stem cells. It is used when stem cells or the bone marrow has been damaged by chemotherapy drugs, radiation therapy or disease (such as cancer). The new stem cells make healthy blood cells.
Allogeneic stem cell transplant uses stem cells from a donor, usually a sibling or someone who isn’t related to the recipient. After the transplant, the donor stem cells make healthy new blood and immune system cells. The new immune system cells attack and destroy CLL cells in the recipient’s body. Unfortunately, the new immune system cells can also attack the recipient’s normal tissues and cause a life-threatening condition called graft-versus-host disease (GVHD). To prevent GVHD, people who receive a stem cell transplant have to take drugs that weaken (suppress) the immune system. But having a suppressed immune system can lead to a greater risk for serious infections. Allogeneic stem cell transplant can also cause serious side effects and is too toxic for older people. For these reasons, and because targeted therapies are effective in treating CLL, allogeneic stem cell transplant isn’t used very often to treat CLL. It may be offered to some people with CLL that is likely to relapse or that is resistant to all the other treatment options available. More research is needed to understand what role allogeneic stem cell transplants may have in treating CLL and who might benefit most from this treatment (Bone Marrow Transplantation, PMID 27941763, PMID 28112746; Blood, PMID 28716861).
Reduced-intensity allogeneic transplant uses lower doses of chemotherapy or radiation therapy before the transplant. The lower doses don’t completely destroy the recipient’s bone marrow, so blood cell counts don’t drop as low as they do in standard stem cell transplants. For this reason, there is a lower risk for complications. Researchers are studying reduced-intensity allogeneic transplants as a way to make stem cell transplants safer, easier and more effective for people with CLL (Biology of Blood and Marrow Transplantation, PMID 27660167; Best Practice and Research: Clinical Haematology, PMID 27742072).
Find out more about research in stem cell transplants.
Living with cancer can be challenging in many different ways. Supportive care can help people cope with cancer, its treatment and possible side effects. The following is noteworthy research into supportive care for CLL.
Ruxolitinib (Jakavi) is a kinase inhibitor used to treat certain blood disorders. Researchers are studying this drug in clinical trials to see if it can help control symptoms in people with CLL (Lancet Haematology, PMID 28089238).
Learn more about cancer research
Researchers continue to try to find out more about CLL. Clinical trials are research studies that test new ways to prevent, detect, treat or manage CLL. Clinical trials provide information about the safety and effectiveness of new approaches to see if they should become widely available. All of the standard treatments for CLL were first shown to be effective through clinical trials.
A substance that can find and bind to a particular target molecule (antigen) on a cancer cell.
Monoclonal antibodies can interfere with a cell’s function or can be used to carry drugs, toxins or radioactive material directly to a tumour.
A condition that might happen after a stem cell transplant. Healthy stem cells from a donor (called the graft) attack a recipient’s (receiver’s) cells (called the host). The graft cells see the host cells as foreign and start to destroy them. Symptoms include jaundice, rash or blisters on the skin, dry mouth or dry eyes.
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