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Breyanzi (lisocabtagene maraleucel), a CAR-T cell therapy, showed benefits for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to recent research published in 

Overall findings have shown that patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have exhausted all other treatments can find improvements within T-cell therapy.

This type of immunotherapy allows for a patient’s own immune cells to fight off the cancer by altering T cells and then re-infusing them back into the body to fight off cancer.

“CAR-T therapy uses the patient’s own immune cells to fight cancer. This novel form of cellular immunotherapy has been a major advance in the treatment of relapsed B-cell lymphomas. Here we reported the first multi-center study of (Breyanzi), a CAR-T therapy in CLL/SLL,” said Dr. Shuo Ma, professor of Medicine in the Division of Hematology and Oncology and a co-author of the study said in a press release issued by Northwestern University Feinberg School of Medicine.

Both CLL and SLL originate in lymphocytes (white blood cells); CLL and SLL are very similar — except for the slight difference of CLL occurring in bone marrow, and SLL occurring within the lymph nodes — and are the most common subtypes of leukemia.

Historically, conventional immunochemotherapy (combining chemotherapy drugs with immunotherapy drugs to strengthen immune system and fight off the cancer) was the main source of care for patients with CLL and SLL. Once oral targeted therapies (drugs taken by mouth, and destroys cancer cells more precisely) have become more popular within the decade, BTK and Bcl-2 inhibitors have become main treatments for patients with CLL and SLL, according the press release.

These treatments do work well, but some patients with higher-risk disease relapse or stop responding to the treatment, being left with very few treatment options.

The study focused on the efficiency and safety of Breyanzi, and included 117 patients with relapsed or refractory CLL and SLL who had received and average of five lines of therapy previously. Every patient within the study was given a Breyanzi infusion, each at one of the two dosage levels being tested within the study, according to the press release.

Among the 49 patients who received the higher dosage, each having double refractory CLL or SLL, there was an overall response rate (percentage of patients whose disease shrunk or disappeared) of 47%, with the complete response and remission rate (meaning that cancer was undetectable after treatment) being 18%. This is differing from historical outcomes with different treatments, which were seen to be between and 0 to 5%, Ma explained.

This study also concluded that the time to response was around a month, and the patients who experienced full remission and response did not relapse within a 20-month period, according to the study.

Immune-related side effects included cytokine release syndrome, which was seen in 9% of the studied patients, and advanced neurological events, which was seen in 18% of the studied patients.

“CAR T-cell therapy is a very promising future treatment option for our patients with CLL/SLL. Future studies are being planned to compare this novel treatment with the existing standard treatments,” said Ma.

For more news on cancer updates, research and education, don’t forget to 

CAR T-cell therapy positively benefitted patients with patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Breyzani Benefits Previously Treated SLL, CLL 

Food and Drug Administration (FDA) approval of Kymriah

 (tisagenlecleucel) for the treatment of certain children and young adults with acute lymphoblastic leukemia, marking the first FDA-approved CAR-T cell therapy for patients with cancer.

Over the past half decade, six CAR-T cell drugs gained FDA approval for various types of leukemias, lymphomas and multiple myeloma, drastically changing the treatment paradigm of patients with blood cancer.

CAR-T cell therapy uses a patients’ own immune system to attack the cancer.

“In CAR-T cell therapy, the ‘CAR’ means chimeric antigen receptor,” 

Dr. Jordan Gauthier of Fred Hutchinson Cancer Center

 in Seattle said in an interview with CURE®. “We use one white blood cell type we call T cells and, we engineer them in the lab to express this new receptor that we call CAR … so we ‘cook’ the cells in the lab until we have enough of them, and then we put them in a bag and infuse them.”

Of note, Gauthier was a member of the Seattle Cancer Care Alliance at the time of the interview. In April, the Seattle Cancer Care Alliance and Fred Hutchinson Research Center united to become one organization known as the Fred Hutchinson Cancer Center.

The CAR-T cell therapy process starts with a blood draw so that clinicians can collect the patients’ white blood cells. The T cells will then be specially engineered to find and attack cancer. Once the killer T cells are made, they will be multiplied.

While T cells are being created, the patient will undergo conditioning chemotherapy treatment, which will kill off other immune cells, essentially “making room” for the engineered T cells to proliferate within the body.

Once the T cells are engineered and the patient has finished conditioning treatment — a process that typically takes a couple of weeks — the CAR-T cells will be infused back into the patient.

At this point, patients and their health care team must 

, namely neurotoxicity (impairment to brain function) and cytokine release syndrome (the release of too many inflammatory molecules into the blood) — both of which could be serious if not caught early.

While prior studies have shown that the majority of patients undergoing CAR-T cell therapy will experience side effects, ongoing research is trying to determine which patients are 

After patients leave the hospital after the side effect monitoring period is over, they may not need to return for more treatment, as CAR-T cell therapy often offers patients a 

 with lasting efficacy and cancer control, explained Dr. Lori A. Leslie, director of the Indolent Lymphoma and CLL Research Program at John Theurer Cancer Center in Hackensack, New Jersey.

 may qualify for CAR-T cell therapy, researchers are still studying 

, as well as investigating CAR-T cell therapy’s potential in different cancer types — 

Additionally, this summer, the FDA agreed to speed up their review of a 

 to treat rare forms of lymphoma and leukemia.

“We've started to see some patients with very long-term remissions now from CAR T. So I'm excited to see the how that field evolves in the coming years,” 

said Dr. Matthew Davids, of the Dana-Farber Cancer Institute

 in Boston, in an interview with CURE®. “I'm excited to see the how that field evolves in the coming years.”

Over the past five years, CAR-T cell therapy has improved outcomes for many patients with blood cancer. Here’s what patients need to know about the immune-based treatment.

What Is CAR-T Cell Therapy, and What Can Patients With Cancer Expect?

Cancer treatment almost always comes with side effects, regardless of how the disease is treated; chemotherapy, radiation therapy and immunotherapy all have their drawbacks.

Chemotherapy may cause hair loss, nausea and fatigue, whereas immunotherapy can cause lowered blood cell counts. But one significant side effect often occurs, paradoxically, as a result of successful treatment.

Tumor lysis syndrome is a dangerous oncological emergency that occurs when rapidly dying tumor cells release toxins into the bloodstream. This often happens as a response to effective treatment, but it can also happen spontaneously. The phenomenon tends to be more common in patients with a diagnosis of lymphoma or leukemia compared with other types of cancer. It can cause organ damage, and even be fatal. However, experts say that tumor lysis syndrome is well understood and can usually be effectively treated and prevented.

“Tumor lysis syndrome is when a patient with cancer is receiving a therapy, such as chemotherapy or other drugs, and the treatment is working so well that it’s actually breaking the tumor cells open too quickly,” explained Dr. Matthew S. Davids, associate professor of medicine at Harvard Medical School and director of clinical research in the division of lymphoma at Dana-Farber Cancer Institute in Boston, in an interview with CURE®. “And the tumor cells have toxins inside them. They have different types of salts, like electrolytes, and when those toxins and salts get spilled into the blood too quickly it overwhelms the body’s ability to clear them out.”

These electrolytes, particularly potassium and phosphate, would normally be handled by the kidneys and eliminated from the body in a patient’s urine. But, when the levels of these waste products become too great for the kidneys to handle, they can cause organ damage.

“The kidneys can’t clear out the toxins, and that can lead to serious issues for patients,” Davids continued. “This can include things like kidney issues or even heart issues. In its most serious forms, tumor lysis syndrome can even be life-threatening or fatal, but it also has milder forms where we only see these lab changes, and we can address them, and patients can still do very well.”

Notably, patients with lymphoma and leukemia are at particular risk because these blood cancers can be particularly sensitive to certain treatments and often come with a high tumor burden, meaning there are large numbers of tumor cells in a person’s body. 

One study of patients with chronic lymphocytic leukemia who were treated with the drug Venclexta (venetoclax) found that 2.7% of patients developed clinical tumor lysis syndrome, meaning these patients showed both high levels of toxins in a blood test and clinical complications, while 5.7% of patients had tumor lysis syndrome as determined by lab work.

Another study of patients with acute myeloid leukemia treated with Venclexta and either Vidaza (azacitidine) or Dacogen (decitabine) found that 18% of patients developed tumor lysis syndrome according to their bloodwork; 5% of patients developed clinical tumor lysis syndrome.

In general, research states that 3% to 7% of patients with leukemia and 4% to 11% of patients with lymphoma develop tumor lysis syndrome, though some subtypes of these cancers may have an incidence as high as 25%.

The symptoms of tumor lysis syndrome are vague and nonspecific, meaning patients are unlikely to identify it themselves, or know which signs to look out for. People with tumor lysis syndrome show symptoms like fatigue or malaise, nausea and vomiting, or sometimes flank pain (pain in one side of the body between the upper stomach area and the back), but these symptoms apply to many situations and will not immediately make a patient think of tumor lysis syndrome.

“There’s really not too much that patients will notice,” Davids noted. “At least not in the early stages.”

The only way to detect tumor lysis syndrome in its early stages is through blood testing. Usually, a patient’s care team will be aware of the risk and will conduct lab testing accordingly. When care providers know a patient is at risk for developing tumor lysis syndrome, they can take steps to prevent it with medicine and make sure the patient is properly hydrated to ensure good kidney function. Once it is diagnosed, clinicians must move quickly to treat it.

“There are really two scenarios in tumor lysis syndrome. There are the outpatients, and that’s who I see,” said Amy Goodrich, a nurse practitioner in the Hematologic Malignancies Program and research nursing manager at The Johns Hopkins Kimmel Cancer Center in Baltimore, in an interview with CURE®. “We do a very good job of preventing tumor lysis syndrome because we have time. We have time to get the medications they need and make sure they’re hydrating and getting them set up to avoid (it).”

But not all patients have the luxury of preparing in advance. When care teams have to administer cancer treatment as soon as possible, a different approach is necessary. These patients are often people with acute leukemias or aggressive lymphomas.

“Then there are inpatients,” Goodrich continued. “In the inpatient setting, those are the super-sick people, the urgent patients, who you don’t have time to get them all those preparations.”

Two main drugs are used to prevent and/or treat tumor lysis syndrome, Goodrich highlighted. Allopurinol is an oral drug that is used as a preventive measure to stop the body from producing uric acid, thereby avoiding buildup of this toxin in the patient’s body. Clinicians will start a patient on allopurinol in the days leading up to chemotherapy and will try to make sure the patient is drinking at least 64 ounces of fluid each day.

Elitek (rasburicase), a drug usually administered intravenously, can rapidly lower a patient’s levels of uric acid, making it a good emergency measure. And there are other drugs that can be used to control a patient’s potassium and phosphate levels. Goodrich added that patients are most likely to experience tumor lysis syndrome during their first cycle of therapy, because this is when their tumor burdens are the greatest.

“By the next time they get treated, their tumor burden is really low and that risk of overwhelming the kidneys is significantly lower,” Goodrich explained.

In some situations, patients may need dialysis to clear the toxins from their blood.

“A nephrologist like me will have to come in and essentially clean up the blood, because with the death of those tumor cells, which is a wanted outcome, we are now dealing with the debris, which the kidney cannot take care of,” said Dr. Khalid Bashir, a nephrologist and associate professor of medicine at Creighton University in Omaha, Nebraska. “(We have to) clean out the extra phosphate, clean out the extra potassium, normalize the calcium.”

He added that generally, preparation and prevention is enough to avoid emergency situations.

“For the most part we don’t have to dialyze them. If we’re called in a timely fashion, this is a very preventable thing. These patients may not go into tumor lysis syndrome,” Bashir continued. “But even if they go into tumor lysis syndrome, despite our interventions with intravenous fluids or medications, if it has overwhelmed patients’ ability to get rid of these waste products, then we have to bring in a machine … and clean out the blood.”

The situation can become dire in a short time, experts say — as little as a matter of hours — but intervention can be handled quickly as well.

“Dialysis is needed, and usually is done, in a very quick fashion,” Bashir added.

Goodrich said patients who are at risk of developing tumor lysis syndrome are generally not adequately informed, but this is not the fault of any person. Rather, she continued, patients may not remember discussing the possibility of tumor lysis syndrome because they are preoccupied with receiving treatment for a deadly disease. Furthermore, getting patients to adhere to preventive measures can be difficult.

“It’s only preventive if they’re taking their allopurinol and hydrating at home,” she said. “It is continuously amazing to me how many people have a cup of coffee in the morning and a little water at dinnertime and that’s all they drink all day. Those folks, it’s a real challenge to get them to hydrate.”

If patients show low-level laboratory tumor lysis syndrome on blood tests but don’t exhibit changes in their kidney or heart function, Goodrich said, they can expect to receive extra fluids and medications in an outpatient setting. If clinicians notice abnormal heart or kidney function, however, the patient will be admitted to the hospital.

Davids says he advises patients about the possibility of tumor lysis syndrome, but only in situations where it is likely to happen.

“I only tell patients about it if I think it’s a significant risk to an individual,” he said.

Davids also emphasized that tumor lysis syndrome is a byproduct of successful treatment.

“Although tumor lysis syndrome seems very scary, which it can be, the flipside of it is that it suggests the cancer therapy is working extremely well,” he concluded. “Having a little bit of tumor lysis syndrome, as long as it’s very closely monitored and managed, may not be such a bad thing. This is something we’re trained as oncologists to manage.”

Although tumor lysis syndrome may be dangerous and fatal if not treated early, experts note that it is a sign of successful treatment in patients with leukemia and lymphoma.  

The 'Flipside' of Tumor Lysis Syndrome Shows Efficacy in Leukemia, Lymphoma

The development of new treatment options for diffuse large B-cell lymphoma (DLBCL) traditionally has lagged behind other types of blood cancer, but the implementation of targeted therapies and other new clinical trials are starting to move the needle forward for the disease, which is the most common type of non-Hodgkin lymphoma.

Dr. Brian T. Hill, director of the Lymphoid Malignancies Program, recently discussed these exciting updates at the 2022 International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma.

One of the main struggles in treating DLBCL is how similar treatment outcomes are for patients receiving the same standard-of-care therapies, Hill said.

Various factors can indicate the level of risk for patients. International Prognostic Index (IPI) status considers risk based on age greater than 60, poor performance status, advanced stage, serum lactate dehydrogenase above normal limits (which could indicate tissue or organ damage), and at least one extranodal (beyond the lymph nodes) site. Higher IPI is predictive of worse overall survival (OS).

The standard of care for frontline therapy is R-CHOP, a drug combination of Rituxan (rituximab), cyclophosphamide, doxorubicin, vincristine and prednisone), which is typically given once a day every three weeks for six cycles. A viable alternative is dose-adjusted R-EPOCH (Rituxan, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) regimen given as continuous infusions over four to five days every three weeks for six cycles, with dose escalation every cycle.

For double-hit lymphoma (where there are rearrangements in two genes), which is especially high-risk, data suggest that intensive induction regimens such as R-EPOCH are more effective than R-CHOP. Only 10% of patients who have double-hit lymphoma will receive R-EPOCH as opposed to R-CHOP in most cancer centers.

R-CHOP and R-EPOCH were directly compared in the A50303 trial, but the results were negative.No statistically significant difference was found in terms of OS, with a two-year OS rate of 86.5% for R-EPOCH and 85.7% for R-CHOP. Hill noted that this trial may have been influenced by factors such as having a longer period of time before patients started receiving treatment, which may have led to enrolling patients with more favorable risk.

Polivy PFS Improvement Challenges Standard of Care

One of the most important changes to standard of care in upfront therapy has been the introduction of Polivy (polatuzumab vedotin), an antibody-drug conjugate that targets CD79B, a component of the B-cell receptor signaling apparatus.

In the relapsed/refractory setting, a phase 2 trial compared Polivy with bendamustine and Rituxan versus bendamustine and Rituxan alone. Though it was a small study, Hill points out a higher number of complete responses (CR) with Polivy /bendamustine/Rituxan in the patients with ABC versus GC DLBCL. There were no differences in subgroups in the Polivy group.

Based on the positive outcomes with Polivy in the relapsed setting, vincristine was substituted from the R-CHOP regimen to create the Polivy -R-CHP regimen, and the two regimens were compared directly in previously-untreated patients in the phase 3 POLARIX trial. The two-year progression-free survival (PFS) rate, defined as the average time from treatment until patients’ disease gets worse, was 76.7% with Polivy-R-CHP versus 70.2% with R-CHOP, favoring Polivy.

Subgroup analysis showed that patients with high IPI score had better outcomes with Polivy-R-CHP, and those in the ABC group fared better with Polivy despite their expected higher risk. However, there was no OS advantage in this trial.

Based on the subsequent treatments received by the patients in each arm of POLARIX, Hill suggested that in approximate terms, several times as much money was spent to prevent relapse in those who received R-CHOP versus those receiving Polivy-R-CHP, which could warrant more investigation of costs and benefits of treatment.

In his presentation, Hill proposed the development of five new comparison trials for patients with each of 5 molecular subtypes that would compare Polivy-R-CHP plus a targeted inhibitor versus Polivy-R-CHP alone. If these trials show differences in outcomes due to the targeted therapy, patients could be treated more effectively upfront based on the results of genetic testing.

“DLBCL is not a single entity but largely approached this way clinically in 2022. While in general GC-derived tumors have better outcomes than those derived from ABCs, there is a heterogeneity which can be explained in the subgroup analysis,” Hill concluded. “Future clinical trials should be based on integration of multiomic biomarkers to test precision medicine with specific pathway inhibitors for individual subtypes of DLBCL.”

An expert gives an overview of current standard of care and what’s coming down the pipeline in terms of treatment options for diffuse large B-cell lymphoma. 

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