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Knowing MRD Status Can ‘Increase Chance of Cure’ in Blood Cancer

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 Food and Drug Administration (FDA) gave the OK for clinical trials investigating magrolimab plus Onureg (azacytidine) for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) to resume.

The phase 3 ENHANCE, phase 3 ENHANCE-2, phase 3 ENHANCE-3, phase 1b study in MDS and phase 2 studies in myeloid 

 in January after an imbalance of investigator-reported suspected unexpected serious side effects.

There are also ongoing studies of magrolimab for the treatment of solid tumors that were never put on clinical holds.

The FDA recently reviewed comprehensive safety data from the trials and lifted the partial clinical hold on the ENHANCE trial, and will work with Gilead Sciences Inc., the manufacturer of magrolimab to address the partial clinical holds on other trials.

“Our confidence in the risk-benefit profile of magrolimab has been unwavering, and we continue to believe in the potential for this treatment to address the unmet medical needs faced by people living with MDS and AML,” Dr. Merdad Parsey, chief medical officer of Gilead Sciences, said in a press release.

Patients who were enrolled in the ENHANCE trials before the partial clinical hold was placed were still able to continue to receive treatment with the drug, though the hold meant that no new patients could be added to the study. Since enough patients were already on the trial to conduct an interim analysis, Gilead Sciences states that the company should still be able to publish early data from the study in 2023.

Magrolimab is a monoclonal antibody that works by inhibiting CD47, a protein that tells the immune system not to attack. By blocking it, magrolimab allows macrophages (a type of white blood cell that kills and removes cells and stimulates the immune system) to attack the cancer.

“This is a significant milestone … for patients diagnosed with these cancers. We look forward to continuing our work developing magrolimab and advancing this potential cancer treatment option,” Parsey said.

Earlier in the year, clinical trials assessing magrolimab for myelodysplastic syndrome and acute myeloid leukemia were put on a partial clinical hold, but now the FDA said that they can start enrolling patients again. 

FDA OKs Continued Enrollment in Ongoing Blood Cancer Clinical Trials After Gilead Addresses Safety Concerns

For many patients with blood cancers, an allogeneic stem cell transplant offers them the opportunity to potentially have their disease cured. However, the process comes with its own set of risks, too — mainly a condition called graft-versus-host disease (GVHD), where a patient’s body rejects and attacks the donor.

GVHD can be severe — or even fatal — though medical advancements in recent years have fine-tuned the way that it is treated, leading to better outcomes for patients with the condition, explained Dr. Scott D. Rowley, a professor of Medicine at Georgetown University School of Medicine in Washington.

“Allogeneic transplant is known to have a very potent graft-versus-tumor effect with the idea that this immunological response can lead to cure of an underlying hematological disease. But we do have our complications,” Rowley said.

Rowley, who is also a hematologist oncologist at John Theurer Cancer Center in Hackensack, New Jersey, and Lombardi Comprehensive Cancer Center, recently discussed new and emerging treatments for GVHD at the 26th Annual International Congress on Hematologic Malignancies.

Acute GVHD occurs when a patient develops GVHD within 100 days after their transplant. This December, the Food and Drug Administration (

FDA) approved Orencia (abatacept) plus another immunosuppressive drug

 to prevent acute GVHD in children (aged 2 or older) or adults who underwent a hematopoietic stem cell transplant from an unrelated donor.

Orencia works by inhibiting T-cell activation and B-cell immunological response — two processes that contribute to the body’s response against donor cells.

“(Researchers) found that adding (Orencia) greatly reduced the risk of severe graft-versus-host disease. What’s more interesting is that at 180 days out, even with a mismatch (donor), there was a very high degree of preventing severe, acute GVHD,” Rowley explained.

Also approved for acute GVHD is Jakafi (ruxolitinib). This approval was based on an open-label, phase 3 clinical trial that showed that Jakafi can treat chronic GVHD that was not responsive to steroids, which is typically the first line of treatment against the condition.

“There was a higher (complete response) rate with the addition of (Jakafi) and then maintaining the acute GVHD-free survival,” Rowley said.

There are now more drugs than ever to treat and prevent graft-versus-host disease in patients with blood cancer who receive a stem cell transplant. 

Leukemia

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