Dec. 09, 2025
Advances in chronic lymphocytic leukemia (CLL) therapies over the last 10 years are rewriting the script on how people today are living with the disease.
"When I see patients with CLL, I'm able to tell them it's a slow-growing lymphoma," says Ricardo D. Parrondo, M.D., a hematologist-oncologist who specializes in chronic lymphocytic leukemia (CLL) at Mayo Clinic Comprehensive Cancer Center in Jacksonville, Florida. "They might not need treatment for many years and, even when they do, the therapies we have now are going to help them prolong their lives by decades and, more importantly, live much better."
CLL overview
CLL is the most common type of leukemia in adults in the United States. Yet with roughly 25,000 diagnoses a year, it's generally considered rare, Dr. Parrondo says. While CLL is indolent, managing the disease requires expertise and a deep understanding of rapidly evolving treatment options.
At Mayo Clinic in Florida, Dr. Parrondo and his team specialize in CLL and small lymphocytic lymphoma (SLL), working within a multidisciplinary, disease-focused program to individualize treatment and expand access to emerging therapies through clinical trials.
In fact, Dr. Parrondo says, "Many of the innovations over the last years in CLL were evaluated at Mayo Clinic in Florida, and they've really made the lives of patients much better."
CLL and SLL represent different manifestations of the same disease, distinguished primarily by the location where the cancerous lymphocytes are most abundant. In CLL, the cells are predominantly found in the blood and bone marrow. In SLL, the cells are concentrated mostly in the lymph nodes.
Still, CLL and SLL are treated the same way, and many patients are asymptomatic at the time of diagnosis, requiring only active surveillance.
"If patients just need observation, they're pretty much able to carry on with life as normal," Dr. Parrondo says. "Once they develop symptoms, we initiate treatment, and the symptoms improve within a matter of weeks or months. The fatigue goes away, the lymph nodes shrink in size, the spleen shrinks in size, the blood counts get better and patients stay in remission for many, many years."
Targeted agents as frontline therapy
Before 2015, the standard-of-care treatment for CLL was chemotherapy, Dr. Parrondo says, which can come with high toxicity and a host of side effects such as hair loss. The tide began to turn after 2014, when the U.S. Food and Drug Administration (FDA) approved the use of the first Bruton tyrosine kinase (BTK) inhibitor for treating hematologic malignancies such as CLL. BTK inhibitors work by blocking the B-cell receptor signaling pathway. Then in 2016, the FDA approved the first B-cell lymphoma 2 (BCL-2) inhibitor drug for the disease. BCL-2 inhibitors target BCL-2 proteins that are particularly abundant in CLL cells.
Today, these orally administered therapies are typically used as first line treatment for CLL, and are often given sequentially over the course of the disease. If patients develop drug resistance to the treatments, CAR-T cell therapy and bone marrow transplant — typically, allogeneic hematopoietic stem cell transplant — are secondary options.
"We almost never use chemotherapy anymore," Dr. Parrondo says. "The targeted therapies we have are more effective and better tolerated. Because of these, patients are able to continue working, traveling and spending time with family."
Expanding access through clinical trials
In addition to these standard-of-care targeted and cellular therapy options, Mayo Clinic in Florida participates in and leads multiple clinical trials across the spectrum of CLL care, from treating newly diagnosed patients to managing those with relapsed and refractory disease.
"We have clinical trials in every phase happening at the same time," Dr. Parrondo says. "Patients may have the opportunity to receive investigational agents not available elsewhere. And the drugs that are standard of care today were once given to patients in clinical trials. Clinical research is how innovation reaches our patients."
Dr. Parrondo emphasizes that phase 1 trial design prioritizes safety and is guided by careful dose escalation.
"Patients sometimes worry about being the first to receive a drug," he says. "But these therapies are extensively studied before reaching human trials, and we start with very low doses. It's a structured, stepwise process."
Emerging therapies: Bispecific antibodies and next-generation inhibitors
Bispecific antibodies, which link malignant B cells to cytotoxic T cells to enhance targeted immune killing, are now approved for several hematologic malignancies, including multiple myeloma. While not yet approved for CLL, bispecific agents are under active investigation at Mayo Clinic in Florida.
"We are opening bispecific clinical trials for patients with CLL," Dr. Parrondo says. "These drugs are very promising and may expand treatment options for patients who have exhausted current therapies."
Other promising novel treatment approaches currently under investigation for CLL include new monoclonal antibodies, small-molecule inhibitors such as BTK degraders, and agents targeting angiogenesis and DNA damage repair.
Multidisciplinary expertise and coordinated care
Blood cancer management at Mayo Clinic in Florida is organized into disease-specific care teams. For that reason, the structure supports rapid diagnostic confirmation, discussion of complex disease across Mayo Clinic sites and individualized treatment planning, Dr. Parrondo says.
"You want to see a physician who specializes in your specific cancer so the physician can tailor the treatment or the observation specifically to you and your needs," he says. "Each cancer is different, so even across different patients, we personalize the therapy to each patient. Because we have a big, multidisciplinary team, everything is specialized — from the appointment to the management services to the nurses, doctors and nurse practitioners."
Mayo Clinic collaborates closely with referring hematologists and oncologists, with many patients receiving portions of their care locally while treatment planning and disease monitoring typically occur in partnership.
"I view the referring clinician as an integral part of the team," Dr. Parrondo says. "If patients live hours away, we can evaluate them here, make recommendations and stay involved through telemedicine. Our goal is to support both patients and their doctors."
Referral considerations
Because CLL is relatively rare, Dr. Parrondo encourages referral when diagnostic clarity, treatment sequencing or access to clinical trials is needed.
"If there's any uncertainty, send the patient to us," he says. "We will provide a comprehensive evaluation and work collaboratively. Patients can usually be seen quickly, and we'll help determine whether treatment is needed and what options are appropriate."
For more information
Learn more about CLL clinical trials at Mayo Clinic in Florida.
Refer a patient to Mayo Clinic.