First-Ever CAR-T Therapy Approved for CLL, SLL

The U.S. Food and Drug Administration (FDA) has approved lisocabtagene maraleucel (liso-cel; brand name Breyanzi) for patients who have chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) and have tried at least two lines of therapy. It is the first chimeric antigen receptor T-cell (CAR-T) therapy approved for these patients.

“Remarkable Breakthrough”

The approval was based on the phase 1/2 TRANSCEND CLL 004 trial, which met its primary endpoint of complete response, meaning that all signs of cancer were gone for some patients. The findings were published in The Lancet in June 2023.

The announcement represents a huge breakthrough in treating CLL/SLL, experts say.

“CLL and SLL are currently considered incurable diseases with few treatment options in the relapsed setting that can confer complete responses,” lead investigator Tanya Siddiqi, MD, associate professor in the division of lymphoma at City of Hope National Medical Center in Duarte, California, said in a press release from the manufacturer, Bristol Myers Squibb.

The approval represents “a remarkable breakthrough, shifting the treatment paradigm from continuous therapy with sequential regimens to overcome drug resistance, to a one-time personalized T-cell based approach that has the potential to offer patients complete and lasting remission,” she said.

20% in Trial Saw Complete Response

The complete response rate associated with liso-cel in the TRANSCEND trial was 20%. Among all patients who responded, the median duration of response was 35.3 months. High rates of minimal residual disease (MRD) negative status were seen for patients treated with liso-cel who achieved a complete response. with an MRD-negativity rate of 100% in the blood and 92.3% in bone marrow. An MRD-negative result means no disease was detected after treatment.

Two CLL survivors who had CAR-T in a clinical trial tell Patient Power about how the infusion made it possible for them eventually to stop all medications for CLL.

Treatment Has Boxed Warnings

The safety information for liso-cel includes boxed warnings regarding cytokine release syndrome (CRS), neurologic toxicities, and secondary hematological malignancies.

Among 89 patients in the study treated with liso-cel, occurrences of CRS and neurologic events (NEs) were mostly low grade, the company states in the press release. Any-grade CRS occurred in 83% of patients, grade 3 CRS occurred in 9% of patients, and no grade 4/5 CRS events were reported. Any-grade NEs were reported in 46% of patients, grade 3 NEs were reported in 20% of patients, one case of grade 4 NE was reported, and no grade 5 Nes (death from Nes) were reported.

How the Treatment Works

With CAR-T, a one-time treatment, some of your own white blood cells (T-cells) are taken from your body, genetically changed in a laboratory to recognize and attack your lymphoma cells, and then returned to your bloodstream to fight your cancer.

Bruton tyrosine kinase inhibitors (BTKs) and venetoclax are currently used to treat CLL and SLL, but most patients eventually develop resistance to these therapies.

CAR-T has brought promising new options for treating other cancers, including multiple myeloma. With this approval, it becomes an option for some patients with CLL/SLL.

FDA Expanding Uses for the Drug

Liso-cel was previously approved to treat adults with large B-cell lymphoma (LBCL). The FDA’s action March 14 expands the indication to patients who have CLL/SLL that has relapsed or is hard to treat and who have already been treated with a Bruton tyrosine kinase (BTK) inhibitor and a B-cell lymphoma 2 inhibitor. No standard of care has been established for relapsed or refractory CLL or SLL after a patient has been treated with targeted agents.

The FDA notes that although the agency has granted accelerated approval based on response rate and duration of response, continued approval may be contingent on proven clinical benefit seen in later trials.

How Do Patients Get the Treatment?

According to the manufacturer, there are several steps to getting this treatment. It is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called BREYANZI REMS.

For CAR-T therapy, your blood is drawn at a manufacturing site and goes through a process called leukapheresis, which separates white cells from red cells. The white cells are used to help make the treatment.

After the blood collection at a manufacturing site, it takes about three to four weeks for your cells to be modified and shipped back to your healthcare provider; however, the time may vary.

Before you get the treatment, you will receive three days of chemotherapy to prepare your body by lowering the number of other immune cells. This chemotherapy is used to suppress your own immune system and make room for the CAR T cells to replicate and persist. Once the CAR T cells start binding with cancer cells, they start to multiply and destroy even more cancer cells.

After the chemotherapy is over, you’ll receive pre-medications to lessen adverse reactions. Then, after three to seven days have passed, your provider will give the treatment to you through a catheter in your vein in two different infusions. You will get an infusion of one cell type followed immediately by infusion of another type – usually less than 15 minutes for each of the two cell types.

Side Effects

According to the manufacturer, the treatment can cause:

• Difficulty breathing

• Fever (100.4°F or higher)

• Chills/shaking

• Confusion

• Severe nausea, vomiting, diarrhea

• Fast or irregular heartbeat

• Dizziness or lightheadedness

• Severe fatigue or weakness

Tell Your Doctor About Medical Issues

The manufacturer advises that before getting the medication you tell your doctor about:

• Neurologic problems (such as seizures, stroke, or memory loss)

• Lung or breathing problems

• Heart, liver, or kidney problems

• A recent or active infection

The medications you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements

No Driving Advised for Eight Weeks Afterward

Because the drug could cause NEs, including altered mental status or seizures, patients who receive the drug are advised not to drive for at least eight weeks after receiving the infusion.

Announcement Brings “New Hope”

Brian Koffman, MD, retired family physician, CLL patient, and cofounder, executive vice president, and chief medical officer of CLL Society described the importance of Thursday’s announcement.

“The approval of Breyanzi as the first CAR T-cell therapy available for relapsed or refractory CLL or SLL brings new hope to these patients, with the potential for durable responses after a single CAR-T infusion. We are grateful to the patients and their families who enter the trials and to all the researchers involved in making possible this important new treatment option in CLL and SLL,” he said in the press release.